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Strategies to limit life-long dependence on antiretroviral therapy (ART) are needed. We randomized 81 human immunodeficiency virus (HIV)-infected subjects to 4 interventional arms involving continued ART plus ALVAC vCP1452 (or placebo) with or without interleukin (IL)-2 infusions. Viral load rebound 12 weeks after ART interruption was then analyzed to assess immune control. Fifty-two subjects reached the study end point. ALVAC recipients had 0.5 log(10) lower virologic rebounds (P=.033). IL-2 plus vaccine boosted CD4(+) T cell counts (P<.001) but did not diminish viral rebound. Significant changes were not detected for HIV-specific lymphoproliferative responses in any arm. This exploratory protocol provides useful clinical data for future therapeutic immunization trial design. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Objective. Uncontrolled studies have suggested a benefit, after treatment discontinuation, of initiating highly active antiretroviral therapy (HAART) during primary human immunodeficiency virus (HIV) infection. We assessed whether initiation of HAART within 2 weeks of (acute treatment) or between 2 weeks and 6 months after (early treatment) HIV seroconversion was associated with improvements in the viral load and the CD4(+) T cell count after discontinuation of treatment in an observational cohort. Methods. Subjects from the multicenter Acute Infection and Early Disease Research Program cohort were enrolled in the present study within 6 months of HIV seroconversion and self-selected whether to initiate HAART. Subjects who received acute (n=13) or early (n=45) treatment received HAART for at least 12 weeks and then subsequently stopped treatment, whereas untreated subjects (n=337) declined treatment. HIV RNA levels and CD4(+) T cell counts at 24, 48, and 72 weeks after treatment cessation in the 2 treatment groups were compared with those noted in the untreated group during the same periods of observation after enrollment. Results. The acute treatment group had lower mean HIV RNA levels at 24 weeks without therapy (-0.48 log(10) copies/mL [95% confidence interval {CI}, -0.82 to -0.13 log(10) copies/mL]) and higher mean CD4(+) T cell counts (112 cells/ microL [95% CI, 20-205 cells/ micro L]), compared with the untreated group at 24 weeks. The differences in the laboratory values for the acute treatment group versus the untreated group at 72 weeks without therapy were as follows: for the HIV RNA level, -0.35 log(10) copies/mL (95% CI, -0.91 to 0.21 log(10) copies/mL) and, for the CD4 T(+) cell count, 112 cells/ micro L (95% CI, -15 to 213 cells/ micro L). The early treatment group had lower HIV RNA levels at 24 weeks than did the untreated group, but differences were no longer apparent by week 48; CD4(+) T cell counts were higher in the early treatment group at week 24 (116 cells/ micro L [95% CI, 75-157 cells/ micro L]) and week 72 (70 cells/ micro L [95% CI, 2-138 cells/ mmicro L]). Conclusions. Initiation of HAART within 2 weeks of antibody seroconversion was associated with viral load and CD4(+) T cell count benefits for 24 weeks after termination of HAART, with there being trends toward a longer-term benefit. Later initiation of HAART was associated with a persistent but decreasing CD4(+) T cell count benefit and a loss of the viral load benefit by week 72 after discontinuation of treatment. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

The importance of functional CD4+ T cells and antigen control in the maintenance of CD127 expression on antigen-specific CD8+ T cells is poorly understood in humans. We compared CD127 expression on antigen-specific CD8+ T cells in 4 groups of human immunodeficiency virus (HIV)-infected patients. This analysis demonstrated that HIV-specific CD8+ CD127(hi) T cells are maintained as long-lived memory cells only in HIV-infected individuals treated early with antiretroviral therapy (ART). This population of CD127(hi) T cells fluctuates with viral load (VL) such that the antigen-specific T cell pool oscillates from a CD127(hi) memory to a CD127(lo) effector phenotype depending on the levels of plasma VL. In individuals with chronic infection, the CD127(hi) pool diminishes or is lost with time despite virologic control while receiving ART. These studies show that functionally competent subsets of antigen-specific memory CD8+ T cells in HIV-infected individuals are maintained but only if control of viremia is attained early during the course of infection. Copyright © 2007 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

HIV diagnosis and presentation to appropriate medical care during early stages of disease has substantial clinical and public health benefits. However, a large proportion of HIV-infected Americans experience diagnosis and treatment related delays. Prior research evaluating barriers to early HIV diagnosis and care presentation have been published primarily from large East and West coast urban centers. Therefore, predictors of delayed presentation to HIV care identified by these studies may not be generalizable to the South where infected persons are increasingly non-white, female, poor, non-urban, and possibly exposed to HIV heterosexually. We review here the benefits conferred by HIV care, descriptive epidemiology of delayed HIV diagnosis and care, and potential barriers to early medical care with special reference to conditions prevalent in the South. [ABSTRACT FROM AUTHOR]

Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4+ T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4+ T-cell counts of ≤350 cells/μL), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4+ T-cell counts of ≥500 cells/μL) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T-cell recovery. Furthermore, purified anti-CD4 IgG from HIV-positive immunologic nonresponders induced natural killer (NK) cell-dependent CD4+ T-cell cytolysis and apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. We also found that anti-CD4 IgG-mediated ADCC exerts greater apoptosis of naive CD4+ T cells relative to memory CD4+ T cells. Consistently, increased frequencies of CD107a+ NK cells and profound decreases of naive CD4+ T cells were observed in immunologic nonresponders as compared to responders and healthy controls ex vivo. These data indicate that autoreactive anti-CD4 IgG may play an important role in blunted CD4+ T-cell reconstitution despite effective ART., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

It is well established that retention in high-quality care and regular visits with an HIV/AIDS provider improve outcomes for people living with HIV/AIDS (PLWHA). However, nationally and regionally in South Carolina, retention rates remain low. We piloted an outreach program focused on characterizing out of care (OOC) patients to identify PLWHA who were lost to care and attempt reengagement through phone call, letter, and home visit interventions. Primary outcomes were reengagement, defined as attendance to a clinic appointment, and retention in care, defined by the Health Resources and Services Administration (HRSA) definition (two visits at least 90 days apart in 2015). There were 1242 adult clinic patients in 2014. A total of 233 patients were included in the OOC cohort, according to the inclusion criteria. Of these 233, the outreach coordinator found that a majority of patients, 119 (51%), were lost to care. Reengagement was seen in 52 (44%) patients lost to care, and among those who reengaged, 26 (50%) were retained in care in 2015. This report represents one of few interventions that target reengagement for patients who are lost to care. The use of an outreach coordinator was successful in reengaging and retaining patients in care. It represents an uncomplicated intervention, functional within the current clinic design and available funding structure of the Ryan White grant. Poor engagement and retention in care continue to be significant problems among PLWHA with resultant poor clinical outcomes. Continued focus on new interventions to improve retention in care is necessary to improve clinical outcomes.

Background: Actinomyces, particularly Actinomyces israelii, may cause indolent, persistent infections or represent normal mucosal flora, leading to management dilemmas., Materials and Methods: Prompted by a refractory Actinomyces meyeri infection complicating AIDS, clinical data for all Actinomyces isolates at our hospital laboratory since 1998 were analyzed., Results: A total of 140 cases had a positive result for Actinomyces cultures. Of 130 cases with adequate follow-up, 36 (28%) cases had end-organ or disseminated disease treated with prolonged antibiotics or surgery or both (Group 1). A. meyeri was more common than A. israelii (33% versus 8%; P < 0.05) in Group 1, particularly thoracic infections. Another 56 (43%) cases were considered local pathogens, treated with drainage only or short-course antibiotics (Group 2). Another 38 (29%) cases were deemed commensals (Group 3). Immunosuppression was less frequent in Group 1 versus Group 2 or 3 (P = 0.05) and human immunodeficiency virus or AIDS was uncommon. Foreign bodies or devices (Group 1 versus Group 2 or 3, P = 0.003) and alcoholism (Group 1 versus Group 2 or 3; P = 0.03) were associated with actinomycosis. Isolates from the central nervous system and musculoskeletal sites were more often treated as definitive disease; skin, abdominal or pelvic or single blood culture isolates were more likely commensals (all P < 0.05). Disease progression or recurrence did not occur in Groups 2 and 3, whereas Group 1 had complex and variable courses, including 2 deaths., Conclusions: In the absence of disseminated or end-organ disease, avoiding prolonged therapy for Actinomyces isolates was not associated with adverse outcomes. Alcoholism or foreign bodies were associated with actinomycosis. A. meyeri may be a more common cause of actinomycosis than previously recognized., (Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: There is increasing recognition of the role of B cell dysfunction in HIV pathogenesis, but little is known about how these perturbations may influence responses to vaccinations., Methods: Healthy controls (n=16) and antiretroviral therapy (ART)-treated aviremic HIV-infected subjects (n=26) receiving standard-of-care annual influenza vaccinations were enrolled in the present study. Total bacterial 16S rDNA levels were assessed by quantitative polymerase chain reactions in plasma. Serologic responses were characterized by ELISA, hemagglutination inhibition assay (HI), and microneutralization, and cell-mediated responses were assessed by ELISPOT (antigen-specific IgG+ antibody-secreting cells (ASCs)) and flow cytometry at pre-vaccination (D0), day 7-10 (D7) and day 14-21 (D14) post-vaccination., Results: Decreased peripheral CD4+ T cell absolute counts and increased frequencies of cycling and apoptotic B cells were found at baseline in HIV-infected subjects relative to healthy controls. In healthy controls, post-vaccination neutralizing activities were related to the frequencies of vaccine-mediated apoptosis and cycling of B cells, but not to CD4+ T cell counts. In patients, both baseline and post-vaccination neutralizing activities were directly correlated with plasma level of bacterial 16S rDNA. However, overall vaccine responses including antibody titers and fold changes were comparable or greater in HIV-infected subjects relative to healthy controls., Conclusion: B cell function correlates with measures of recall humoral immunity in response to seasonal influenza vaccination in healthy controls but not in ART-treated patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + abacavir/lamivudine arm [dolutegravir + abacavir/lamivudine arm, 16 (4%); efavirenz/tenofovir/emtricitabine arm, 58 (14%)] through W144 [corrected]. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144.

Streptococcus pneumoniae (pneumococcus) remains one of the most commonly identified causes of bacterial infection in the general population, and the risk is 30-100 fold higher in HIV-infected individuals. Both innate and adaptive host immune responses to pneumococcal infection are important against pathogen invasion. Pneumococcal-specific IgA antibody (Ab) is key to control infection at the mucosal sites. Ab responses against pneumococcal infection by B cells can be generated through T cell-dependent or T cell-independent pathways. Depletion of CD4+ T cells is a hallmark of immunodeficiency in HIV infection and this defect also contributes to B cell dysfunction, which predisposes to infections such as the pneumococcus. Two pneumococcal vaccines have been demonstrated to have potential benefits for HIV-infected patients. One is a T cell dependent 13-valent pneumococcal conjugate vaccine (PCV13); the other is a T cell independent 23-valent pneumococcal polysaccharide vaccine (PPV23). However, many questions remain unknown regarding these two vaccines in the clinical setting in HIV disease. Here we review the latest research regarding B cell immune responses against pneumococcal antigens, whether derived from potentially invading pathogens or vaccinations, in the setting of HIV-1 infection., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unlabelled: The effects of heightened microbial translocation on B cells during HIV infection are unknown. We examined the in vitro effects of HIV and lipopolysaccharide (LPS) on apoptosis of CD27+ IgD- memory B (mB) cells from healthy controls. In vivo analysis was conducted on a cohort of 82 HIV+ donors and 60 healthy controls. In vitro exposure of peripheral blood mononuclear cells (PBMCs) to LPS and HIV led to mB cell death via the Fas/Fas ligand (FasL) pathway. Plasmacytoid dendritic cells (pDCs) produced FasL in response to HIV via binding to CD4 and chemokine coreceptors. HIV and LPS increased Fas expression on mB cells in PBMCs, which was dependent on the presence of pDCs and monocytes. Furthermore, mB cells purified from PBMCs and pretreated with both HIV and LPS were more sensitive to apoptosis when cocultured with HIV-treated pDCs. Blocking the interferon receptor (IFNR) prevented HIV-stimulated FasL production in pDCs, HIV-plus-LPS-induced Fas expression, and apoptosis of mB cells. In vivo or ex vivo, HIV+ donors have higher levels of plasma LPS, Fas expression on mB cells, and mB cell apoptosis than controls. Correspondingly, in HIV+ donors, but not in controls, a positive correlation was found between plasma FasL and HIV RNA levels and between Fas expression on mB cells and plasma LPS levels. This work reveals a novel mechanism of mB cell apoptosis mediated by LPS and HIV through the Fas/FasL pathway, with key involvement of pDCs and type I IFN, suggesting a role for microbial translocation in HIV pathogenesis., Importance: This study demonstrates that lipopolysaccharide (LPS) and type I interferon (IFN) play an important role in memory B cell apoptosis in HIV infection. It reveals a previously unrecognized role of microbial translocation in HIV pathogenesis., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Although T cells are the primary and most-studied targets of the Human Immunodeficiency Virus (HIV), B cells, especially memory B lymphocytes, are also chronically depleted in the course of HIV disease. Although the lack of CD4 + T cell help may explain these deficiencies, intrinsic defects in B lymphocytes appear to contribute to B cell depletion and reduced antibody (Ab) production in the setting of HIV, especially of some antigens eliciting T cell-independent responses. The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Toll-Like Receptor (TLR) agonists. The association of enhanced systemic levels of TLR agonists and B cell dysfunction in HIV disease is not understood. This review discusses the potential role of microbial TLR agonists in the B cell depletion, enhanced autoantibody production and impaired responses to vaccination observed in HIV-infected hosts. Increased microbial translocation in HIV infection may drive B cells to produce autoantibodies and increase susceptibilities of B cells to apoptosis through activation-induced cell death. Determining the mechanisms of B cell perturbations in HIV disease will inform the design of novel strategies of improve immune responses to vaccines, reduce opportunistic infections and slow disease progression.

Herpes simplex virus (HSV) infections are highly prevalent and may have devastating consequences if transmitted to newborns. The highest risk of transmission is when the mother has primary HSV infection (rather than recurrence of chronic infection) late in pregnancy. Clinicians should obtain a careful history, performing serologic testing and counseling as appropriate. Delayed diagnosis of neonatal HSV is associated with high mortality. Even with adequate treatment, permanent sequelae, such as cerebral palsy and developmental delay, may occur. Clinicians should develop prudent strategies to avoid primary HSV acquisition during pregnancy, and provide prophylaxis or treatment when indicated.

Understanding the correlates of immunity that control HIV-1 infection is imperative to our understanding of HIV-1 disease and vaccine development. HIV-1-specific cytotoxic T lymphocytes are fundamental to the control of viremia; however, which T-cell repertoire components enact this control remains unclear. We hypothesize that polyfunctional HIV-1-specific CD8 T cells capable of viral control are present in most patients early in infection and these cells are distinguished by their ability to secrete interleukin (IL)-2 and proliferate. We examined HIV-1-specific CD8 T-cell proliferation and cytokine secretion in primary HIV-1 infection (PHI) using known HIV-1 cytotoxic T-cell epitopes to exclude CD4 bystander effect. We found that only a subset of patients with PHI demonstrated "CD4-independent" CD8 proliferation ex vivo. The remainder of the patients lacked HIV-1-specific CD8 T cells with proliferative capacity, even after the addition of exogenous IL-2. Among the proliferators, IL-2 production from the total HIV-specific CD8 T-cell population correlated with proliferation. Surprisingly, though, we did not routinely detect both IL-2 secretion and proliferative capacity from the same antigen-specific CD8 T cells. Thus, there are distinct and heterogeneous populations of CD8 T cells, phenotypically characterized by either proliferation or IL-2 secretion and few with dual capacity. Generation of these responses may be an important measure of HIV-1 control but are not universal after PHI. Furthermore, the heterogeneity of this population suggests that a simple measure of an effective vaccine response remains elusive.

Background: It is unknown whether sex and race influence clinical outcomes following primary human immunodeficiency virus type 1 (HIV-1) infection., Methods: Data were evaluated from an observational, multicenter, primarily North American cohort of HIV-1 seroconverters., Results: Of 2277 seroconverters, 5.4% were women. At enrollment, women averaged .40 log₁₀ fewer copies/mL of HIV-1 RNA (P < .001) and 66 more CD4(+) T cells/μL (P = .006) than men, controlling for age and race. Antiretroviral therapy (ART) was less likely to be initiated at any time point by nonwhite women and men compared to white men (P < .005), and by individuals from the southern United States compared to others (P = .047). Sex and race did not affect responses to ART after 6 months (P > .73). Women were 2.17-fold more likely than men to experience >1 HIV/AIDS-related event (P < .001). Nonwhite women were most likely to experience an HIV/AIDS-related event compared to all others (P = .035), after adjusting for intravenous drug use and ART. Eight years after diagnosis, >1 HIV/AIDS-related event had occurred in 78% of nonwhites and 37% of whites from the southern United States, and 24% of whites and 17% of nonwhites from other regions (P < .001)., Conclusions: Despite more favorable clinical parameters initially, female HIV-1-seroconverters had worse outcomes than did male seroconverters. Elevated morbidity was associated with being nonwhite and residing in the southern United States.

Acute human immunodeficiency virus type 1 (HIV-1) infection is characterized by high levels of immune activation. Immunomodulation with cyclosporine combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of cyclosporine versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4(+) T cell counts. Adjunctive therapy with cyclosporine in this setting does not provide apparent virologic or immunologic benefit.

We describe a mathematical model and Monte Carlo (MC) simulation of viral evolution during acute infection. We consider both synchronous and asynchronous processes of viral infection of new target cells. The model enables an assessment of the expected sequence diversity in new HIV-1 infections originating from a single transmitted viral strain, estimation of the most recent common ancestor (MRCA) of the transmitted viral lineage, and estimation of the time to coalesce back to the MRCA. We also calculate the probability of the MRCA being the transmitted virus or an evolved variant. Excluding insertions and deletions, we assume HIV-1 evolves by base substitution without selection pressure during the earliest phase of HIV-1 infection prior to the immune response. Unlike phylogenetic methods that follow a lineage backwards to coalescence, we compare the observed data to a model of the diversification of a viral population forward in time. To illustrate the application of these methods, we provide detailed comparisons of the model and simulations results to 306 envelope sequences obtained from eight newly infected subjects at a single time point. The data from 68 patients were in good agreement with model predictions, and hence compatible with a single-strain infection evolving under no selection pressure. The diversity of the samples from the other two patients was too great to be explained by the model, suggesting multiple HIV-1-strains were transmitted. The model can also be applied to longitudinal patient data to estimate within-host viral evolutionary parameters.

Background: Reported reasons for change or discontinuation of antiretroviral therapy ([delta]ART) include adverse events, intolerability, and nonadherence. Little is known how reasons for [delta]ART differ by gender., Methods: In a retrospective cohort study, rates and reasons for [delta]ART alterations in a large University-based HIV clinic cohort were evaluated. Logistic regression analyses were used to evaluate the relationship between reasons for [delta]ART and gender. Cox proportional hazard models were used to investigate time to [delta]ART., Results: In total, 631 HIV-positive individuals were analyzed. Women (n = 164) and men (n = 467) were equally likely (53.0% and 54.4%, respectively) to discontinue treatment within 12 month of initiating a new regimen. Reasons for [delta]ART, however, were different based on gender--women were more likely to [delta]ART due to poor adherence [adjusted odds ratio (OR), 1.44; 95% confidence interval (CI): 0.85 to 2.42], dermatologic symptoms (adjusted OR, 2.88; 95% CI: 1.01 to 8.18), neurological reasons (adjusted OR, 1.82; 95% CI: 0.98 to 3.39), constitutional symptoms (adjusted OR, 2.23; 95% CI: 1.10 to 4.51), and concurrent medical conditions (adjusted OR, 2.03; 95% CI: 1.00 to 4.12)., Conclusions: Although the rates of [delta]ART are similar among men and women in clinical practice, the reasons for treatment changes are different based on gender. The potential for unique patterns of adverse events and poor adherence among women requires further investigation.

HIV-1 (and other viral causes of latent, chronic infections) is not a likely candidate for bioterrorism. Scenarios resulting in the introduction of retroviral infections into a large population generally seem impractical and unpredictable as bioterrorist plots, especially relative to the frightening simplicity of deadly anthrax spores or smallpox virions. As evidenced in the above discussion, contaminating the blood supply would require a highly sophisticated plan resulting in effects of rather limited ultimate scope, and would have to evade an extremely effective screening process already in full force. Contaminating other agents given parenterally is also a potential concern, but again the virus has rather fastidious growth characteristics outside of the human host, and even if this could be accomplished it would presumably affect only a very limited number of targeted individuals. Finally, the idea of a kind of"sexual suicide bomber", an individual deliberately introduced into the community to spread a deadly infectious disease might be proposed. However, as discussed in this commentary, the impact of this rather implausible scenario would be substantially delayed, unreliable, and ultimately could be controlled through a heightened response of already existing public health mechanisms. Whereas HIV has resulted in the "perfect storm" of a devastating pandemic, a major cause of worldwide morbidity and mortality that is tremendously challenging to control, it does not match up very effectively with the Centers for Disease Control and Prevention (CDC) Category A definition of an ideal agent of bioterrorism. It is not easily spread through casual or incidental contact and does not cause a substantial immediate death toll. Instead it is spread only through sexual, parenteral, or maternal/fetal transmission, and generally requires a prolonged and variable clinical latency period prior to disease progression and death. The U.S. public health system is already reasonably well equipped to screen, test, and treat HIV infection (although there is undeniably a greater need for community outreach and education). New introduction of HIV infections in the community via a bioterrorism plot might result in a quantitative difference-but not a funda-mental shift in CDC testing and monitoring plans. Thus, HIV does not match up very effectively as a category B agent of bioterrorism. A growing number of antiviral drugs, increasingly tolerable and conveniently dosed, are making the concept of post-exposure (and even pre-exposure) prophylactic HIV therapy a feasible consideration in many circumstances. The high mutability and adaptability of HIV is a key to its success as a chronic, latent pathogen. These characteristics make vaccine and antiviral drug development an ever-present challenge. On the other hand, there are no data to suggest this complex virus could be eas-ily modified so that it would be more easily transmissible or more rapidly, predictably fatal; therefore, making it an unlikely category C agent as well. Indeed, research during the past decade suggests that HIV disease progression is largely dependent on a complex, individualized host/pathogen interaction rather than the presence of a universal viral trait or toxin. The very characteristics that make a universal vaccine or curative treatment for HIV/AIDS so difficult to achieve also make it a rather poor candidate to be predictably manipulated and wielded as a bioterrorist's weapon.

The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.

Objective: Compare the initial phases of virologic decay when acute/early and advanced HIV-infected adults are administered the same treatment regimen., Design: Mathematical modeling of a previously completed prospective treatment pilot study involving treatment-naive patients with early and advanced immunosuppression., Methods: We analyzed data from a treatment protocol in which 18 individuals with acute or recent HIV-1 seroconversion and six patients with advanced AIDS were administered the same four-drug antiretroviral regimen. Initial treatment responses were compared by fitting a mathematical model to frequent viral load measurements in order to calculate the first and second phase kinetics of viral clearance, and also by comparing viral load suppression over 24 weeks. Patients were also comprehensively compared in terms of protease inhibitor drug levels, HIV-specific immune responses at baseline, and the presence of drug resistance-conferring mutations., Results: There was no statistically meaningful difference in first phase clearance of comparable high-level viremia in the two groups, whether protease inhibitor levels were inserted into the model or 100% antiviral drug effectiveness was assumed. In contrast, acute/early patients had inferior sustained responses than advanced patients, reflecting erratic adherence., Conclusions: Despite many years of intervening immune destruction, the initial virologic decay on therapy appears to be the same at the extremes of the HIV disease spectrum.

Background: Despite the proven benefits conferred by early human immunodeficiency virus (HIV) diagnosis and presentation to care, delays in HIV medical care are common; these delays are not fully understood, especially in the southern United States., Methods: We evaluated the extent of, and characteristics associated with, delayed presentation to HIV care among 1,209 patients at an HIV/AIDS Outpatient Clinic in Birmingham, Alabama between 1996 and 2005., Results: Two out of five (41.2%) patients first engaged care only after they had progressed to CDC-defined AIDS. Among these, 53.6% were diagnosed with HIV in the year preceding entry to care. Recent presentation (2002 - 2005), male sex, age > or = 25, Medicare or Medicaid insurance coverage, and presentation within six months of HIV diagnosis were independently associated with initiating care after progression to AIDS., Conclusions: A high proportion of patients entered clinical care after experiencing substantial disease progression. Interventions that effectively improve the timing of HIV diagnosis and presentation to care are needed.

Enfuvirtide (ENF) is the first of a new class of antiretrovirals (ARVs) known as the HIV fusion inhibitors. Two phase III studies of ENF, TORO 1 and TORO 2, demonstrated that ENF given in combination with optimized background (OB) therapy significantly improved virological response, increased the time to virological failure, and increased CD4-cell count compared with OB alone among highly treatment-experienced patients. The present study investigated the long-term clinical outcomes, costs, and cost-effectiveness of ENF. Outcomes, costs, and cost-effectiveness were estimated using a Markov model. Viral suppression and immune reconstitution were determined from the outcomes of the clinical trials. Time to immunological failure, time to AIDS-defining event (ADE), and time to death were estimated based on published mathematical models of disease progression. Costs were based on published estimates of the use and costs of ARVs, cost of managing ADEs, and cost of laboratory and other outpatient services. Cost-effectiveness was calculated as the incremental cost per year of life gained, adjusted for quality of life. The combined effects of an increase in CD4 count and delayed time to virological and immunological failure with ENF + OB were predicted to produce a mean life expectancy of 7.4 years from initiation of therapy, which was 1.8 years (1.5 quality-adjusted lifeyears [QALYs]) greater than the life expectancy associated with OB alone. The incremental cost-effectiveness of ENF + OB was estimated to be Dollars 24,604 per QALY. ENF is projected to increase time to immunological failure, delay onset of new AIDS-defining events, and increase life expectancy by more than 1.5 years among treatment-experienced HIV-infected patients. The cost-effectiveness of ENF is comparable to many existing treatment and prevention management strategies for HIV.

Purpose of Review: Highly active antiretroviral therapy has dramatically improved the outlook for HIV-infected patients. However, there are a number of major challenges in administering this therapy, including the high cost, potential toxicities, drug resistance, and the need for near-perfect adherence. There thus remains a need to develop immune-based therapeutic approaches that may help augment the benefits of highly active antiretroviral therapy or spare requirements for life-long dependence on continuous therapy., Recent Findings: Basic science studies have improved our understanding of the complex immune response necessary to control HIV viremia. The improved tolerability and feasibility of highly active antiretroviral therapy regimens has optimized immunological conditions for testing therapeutic immunization, while also creating a challenge in terms of trial designs that allow researchers to distinguish between the immunological benefits of immune-based adjuvants in combination with highly active antiretroviral therapy versus the therapy alone. Some recent studies have suggested that therapeutic immunization has the potential to modify the natural history of HIV disease favorably, but there are discordant results between studies as well as between surrogate markers and actual clinical outcomes within studies., Summary: There are intriguing hints that therapeutic vaccination may play a role as the era of highly active antiretroviral therapy progresses, especially as new vaccine technologies with the potential to elicit clinically relevant HIV-specific neutralizing antibody and cytotoxic T-cell responses are developed further. Trial designs utilizing 'analytical treatment interruption' should provide a short-term assessment of whether immune-based interventions modify the host's ability to control viremia in the absence of highly active antiretroviral therapy.

Worldwide HIV-1 vaccine efforts are guided by the principle that HIV-specific T cell responses may provide protection from infection or delay overt disease. However, no clear correlates of T cell-mediated immune protection have been identified. Here, we examine in a HLA-B27(+) HIV seronegative vaccinee persistent HIV-specific vaccine-induced anti-Gag CD4(+) and CD8(+) T cell responses. Although these responses exhibited those characteristics (multifunctionality, appropriate memory phenotype, and targeting of epitopes associated with long-term nonprogression) predicted to correlate with protection from infection, the subject became HIV infected. After HIV infection, the vaccine-induced CD8(+) T cells expanded, but both CD4(+) and CD8(+) T cell responses acquired the functional and phenotypic patterns characteristic of chronic HIV infection. The virus quickly escaped the vaccine-induced T cell response, and the subject progressed more rapidly than expected for someone expressing the HLA-B27 allele. These data suggest that control of HIV by vaccine-elicited HIV-specific T cell responses may be difficult, even when the T cell response has those characteristics predicted to provide optimal protection.

Objective: To understand the mechanisms underlying the differential targeting of T-cell responses during HIV-1 disease progression., Design: We performed a cross-sectional analysis of HIV specific CD8 T-cell responses in peripheral blood mononuclear cells (PBMC) obtained from 21 subjects with well characterized acute or early infection and 88 subjects with chronic HIV-1 infection. We also performed a longitudinal analysis of T-cell responses in five early infected subjects one of whom was studied extensively over a 4-year-period., Methods: PBMC were stimulated with pools of peptides encompassing all of the HIV-1 proteins in an interferon-gamma ELISpot assay. A mean entropy score was calculated for each peptide in the HIV-1 genome., Results: The early infected group preferentially targeted variable peptides with higher entropy while responses towards more conserved peptides with lower entropy predominated in the group with chronic infection. In five early infected subjects followed longitudinally, responses to variable proteins declined while those to conserved proteins increased over time. In the subject who was followed for 4 years, epitopes in Vif and Nef were targeted early and escape occurred in three of these four epitopes. During the chronic phase of his infection, the early responses waned with an associated increase in breadth of T-cell responses mainly to Gag and Pol epitopes., Conclusion: Taken together, these data demonstrate that HIV-specific CD8 T cells are directed preferentially to the variable peptides in early infection but diminish in frequency during chronic disease, in large part due to cytotoxic T lymphocyte escape.

Background: Enfuvirtide, a HIV-1 membrane fusion inhibitor, is the first viral entry inhibitor approved for the treatment of HIV-1 infected patients in the USA. Parenteral administration of enfuvirtide in clinical trials has been safe and has resulted in significant decreases in plasma viral load, even in the setting of extensive previous treatment and multi-drug resistance to conventional antiretroviral (ARV) therapy. Previous formulations have required two injections administered twice-daily (BID)., Objectives: The primary objectives of this study were to evaluate the safety, tolerability, and pharmacokinetics of two high-strength 100 mg/ml formulations of enfuvirtide (carbonate [CO(3)] and tromethamine [TRIS] buffer) and of the current formulation (50 mg/ml CO(3) formulation) at doses of 90 mg (deliverable) BID and 67.5 mg (deliverable) BID in treatment-experienced patients., Study Design: This was a phase II, multi-center, open-label, sequential cross-over pharmacokinetic, efficacy, and safety study. Study design included two treatment variables; dose (90 mg or 67.5 mg BID) and formulation (A: 50 mg/ml CO(3), B: 100 mg/ml CO(3) or C; 100 mg/ml TRIS)., Results: Forty-six treatment-experienced participants were sequentially enrolled into three treatment cohorts. All cohorts had similar safety profiles and only one patient discontinued due to an adverse event. Pharmacokinetic data indicated that the high-strength 100 mg/ml CO(3) formulation was bioequivalent to the 50 mg/ml CO(3) formulation whereas the TRIS formulation was not. At 48 weeks, 59.1%, 66.7% and 16.7% had <400 copies per milliliter HIV-1 RNA in the 90 MgCO(3), 67.5 MgCO(3) and 90 mg TRIS cohorts with median suppression of HIV-1 RNA of 2.97, 3.48, and 0.87 log(10)copies per milliliter, respectively., Conclusions: Based upon bioequivalence data and the convenience and similarity in safety and virological effect with the 50 mg/ml formulation, the 100 mg/ml CO(3) formulation was selected for use in clinical efficacy studies of enfuvirtide.

T-1249 is a 39-aa synthetic peptide that inhibits fusion of human immunodeficiency virus (HIV) to the host target cell. A 14-day open-label, phase 1/2 dose-escalation monotherapy study of the safety and antiretroviral activity of T-1249 was performed on 115 HIV-1-infected adults. At baseline, the majority of the patients had advanced HIV disease (baseline median CD4(+) cell count, 57 cells/microL) and had extensive pretreatment (i.e., pre-T-1249) experience with antiretroviral medications (median, 11 antiretroviral drugs). Patients received T-1249 monotherapy by subcutaneous injection, for 14 days, at doses ranging from 6.25 to 192 mg/day. T-1249 was generally well tolerated, and no dose-limiting toxicity was identified. Injection-site reactions were the most commonly reported adverse event (57%). Dose-dependent decreases in plasma HIV-1 RNA load were observed; the median maximum change from baseline across dose groups ranged from -0.29 log(10) copies/mL (95% confidence interval [CI], -0.43 to -0.05 log(10) copies/mL) for the lowest dose to -1.96 log(10) copies/mL (95% CI, -2.02 to -1.37 copies/mL) for the highest dose. These results indicate that T-1249 is a potent new therapeutic agent for HIV-1 infection.

Objectives: The primary objective was to determine the long-term safety of the subcutaneous self-administration of enfuvirtide. Secondary objectives included the determination of enfuvirtide pharmacokinetics and antiviral activity and the immunological response to the enfuvirtide-containing regimen., Methods: A multicenter 48-week uncontrolled open-label rollover study was conducted on 71 HIV-infected adults recruited from previous enfuvirtide clinical trials. Patients with extensive previous use of protease and reverse transcriptase inhibitors received a twice-daily dose of 50 mg enfuvirtide subcutaneously (45 mg deliverable) combined with two or more antiretroviral drugs selected for each individual, guided by resistance testing and previous treatment history., Results: The mean baseline plasma HIV-RNA level was 4.81 log(10) copies/ml and the mean CD4 cell count was 134.8 cells/microl. The majority (86.9%) of treatment-emergent adverse events were grade 2 or less in severity. Injection site reactions were common, but no patients discontinued treatment. A mean HIV-RNA change of -1.33 log(10) was achieved within 14 days of treatment initiation. At week 48, approximately one-third of all patients in the intent-to-treat population maintained significant suppression of plasma HIV RNA, with either less than 400 copies/ml or more than a 1.0 log(10) decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/microl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations., Conclusion: Self-administration of enfuvirtide is not associated with unexpected toxicities for up to one year, and combined with oral antiretroviral drugs was associated with a significant decrease in HIV RNA and an increase in CD4 cell counts.

Neutralizing antibodies (Nab) are a principal component of an effective human immune response to many pathogens, yet their role in HIV-1 infection is unclear. To gain a better understanding of this role, we examined plasma from patients with acute HIV infection. Here we report the detection of autologous Nab as early as 52 days after detection of HIV-specific antibodies. The viral inhibitory activity of Nab resulted in complete replacement of neutralization-sensitive virus by successive populations of resistant virus. Escape virus contained mutations in the env gene that were unexpectedly sparse, did not map generally to known neutralization epitopes, and involved primarily changes in N-linked glycosylation. This pattern of escape, and the exceptional density of HIV-1 envelope glycosylation generally, led us to postulate an evolving 'glycan shield' mechanism of neutralization escape whereby selected changes in glycan packing prevent Nab binding but not receptor binding. Direct support for this model was obtained by mutational substitution showing that Nab-selected alterations in glycosylation conferred escape from both autologous antibody and epitope-specific monoclonal antibodies. The evolving glycan shield thus represents a new mechanism contributing to HIV-1 persistence in the face of an evolving antibody repertoire.

Despite the overall success of antiretroviral medications in reducing the morbidity and mortality associated with HIV infection, many patients on treatment suffer progressive disease due to intolerance or the development of resistant viral strains. Consequently, considerable research focuses on the development of new classes of antiretroviral agents with mechanisms of action different to the current classes. Enfuvirtide (T-20, pentafuside, Fuzeon), the first drug of a new class of antiretroviral medications known as fusion inhibitors, blocks the fusion of the virus particle with the host target cell. The viral entry process begins with the attachment of viral surface glycoprotein gp120 to the host cell CD4 and chemokine receptor sites. Viral gp41 then undergoes a conformational change enabling fusion of both membranes, a critical step in the viral life cycle. Enfuvirtide is a synthetic peptide that binds to gp41, preventing the conformational change required for membrane fusion. Based on potent in vitro activity, a Phase I clinical trial of intravenous enfuvirtide was conducted that demonstrated a substantial decline in HIV plasma viral load in the highest dose group and no serious adverse effects. Phase II trials evaluated regimens of both continuous subcutaneous infusions and intermittent subcutaneous injections. Intermittent injections were pharmacokinetically superior to continuous infusions and were associated with fewer administration difficulties. For some subjects who added enfuvirtide monotherapy to an already failing regimen, the beneficial effect on viral load reduction appeared short-lived, suggesting the development of resistance. Two large randomised clinical trials comparing "optimised background" (best available, individualised regimens based on patient history and resistance assays) versus optimised background plus enfuvirtide have recently shown a significant virological advantage (approximately 1 log(10) difference from controls) at 24 weeks. In all trials to date, very few significant adverse effects have been seen--minor injection site reactions are frequent, but rarely treatment limiting. Based on these studies, enfuvirtide will likely play a significant role in the treatment of patients with limited treatment options.

Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment.

The synthetic peptide T-20 (enfuvirtide) represents the first of a new class of antiretroviral compounds to demonstrate in vivo potency by targeting a step in viral entry. T-20 inhibits a conformational change in the human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein (gp41) that is required for fusion between HIV-1 and target cell membranes. The initial phase I clinical trial of T-20 treatment for HIV-infected patients thus provided a unique opportunity to evaluate the emergence of resistant virus in vivo to this novel class of antiretroviral agents. All four patients who received an intermediate dose of T-20 (30 mg twice daily) had an initial decline in plasma viral load over the first 10 days but a rising trend by day 14, suggestive of selection for resistant virus. Plasma virus derived from patients enrolled in all dosage groups of the phase I T-20 trial was analyzed by population sequencing before and after treatment. While no mutations were found within a highly conserved 3-amino-acid sequence (GIV) known to be critical for fusion at baseline, after 14 days of therapy, virus from one patient in the 30-mg dose group (30-1) developed a mutation in this motif, specifically an aspartic acid (D) substitution for glycine (G) at position 36. Multiple env clones were derived from the plasma virus of all four patients in the 30-mg dosage group. Sequence analysis of 49 clones derived from the plasma of patient 30-1 on day 14 revealed that 25 clones contained the G36D mutation, while 8 contained the V38A mutation. Dual mutations involving G36D and other residues within the HR1 domain were also identified. In 5 of the 49 env clones, other mutations involving residues 32 (Q32R or Q32H) and 39 (Q39R) were found in combination with G36D. Cloned env sequences derived from the plasma virus of subject 30-3 also had single mutations in the GIV sequence (V38M and I37V) detectable following therapy with T-20. The plasma virus from subjects 30-2 and 30-4 did not contain changes within the GIV sequence. To analyze the biological resistance properties of these mutations, we developed a novel single-cycle HIV-1 entry assay using JC53BL cells which express beta-galactosidase and luciferase under control of the HIV-1 long terminal repeat. Full-length env clones were derived from the plasma virus of patients 30-1 and 30-3 and used to generate pseudotyped virus stocks. The mean 50% inhibition concentrations (IC(50)s) for mutants G36D and V38A (patient 30-1) were 2.3 microg/ml and 11.2 microg/ml, respectively, statistically significant increases of 9.1- and 45-fold, respectively, compared with those of wild-type Env. The IC(50) for the V38 M mutation (patient 30-3) was 7.6 microg/ml, an 8-fold increase compared with that of the wild type. The I37V mutation resulted in an IC(50) 3.2-fold greater than that of the wild type. Envs with double mutations (Q32R plus G36D and Q32H plus G36D) exhibited a level of resistance similar to that of G36D alone. These findings provide the first evidence for the rapid emergence of clinical resistance to a novel class of HIV-1 entry inhibitors and may be relevant to future treatment strategies involving these agents.

Although plasma virus load is invaluable for monitoring human immunodeficiency virus (HIV) infection, key pathogenesis events and most viral replication take place in lymphoid tissues. Decreases in virus load associated with therapy occur in plasma and tissues, but persistent latent infection and ongoing viral replication are evident. Many unanswered questions remain regarding mechanisms of HIV-associated lymphocyte depletion, but partial CD4(+) cell reconstitution after therapy likely reflects retrafficking from inflamed tissues, increased thymic or peripheral production, and decreased destruction. Rapid establishment of latent infection and the follicular dendritic cell-associated viral pool within lymphoid tissues suggest that only early intervention could substantially alter the natural history of HIV. If therapy is started prior to seroconversion, some individuals retain potent HIV-specific cellular immune responsiveness that is suggestive of delayed progression. Although complete virus eradication appears out of reach at present, more attention is being directed toward the prospect of boosting HIV-specific immune responses to effect another type of "clinical cure": immune-mediated virus suppression in the absence of therapy.

Objectives: A goal for long-term therapy of HIV infection is immune control of virus replication rather than the somewhat unrealistic aim of complete viral elimination. This paper will review the evidence that the control of viral infection can be achieved by an active CD8+ T-cell-mediated response., Design: This review will draw on both experimental and clinical sources to discuss the potential mechanisms of the immune control., Results: Data indicate that HIV infection can be effectively controlled by HIV-specific CD8+ T-cell-mediated responses. In infected individuals, the development of active cytotoxic T lymphocytes (CTLs, as measured by lytic activity) is associated with the control of viral replication. Within the simian immunodeficiency virus infection model in rhesus macaques, strong CTL responses are similarly associated with effective viral control. In addition, depletion by antibodies of CD8+ T cells within infected macaques results in rapid increases in viral load. However, in most HIV-infected individuals, the CD8+ T-cells response is inefficient at low antigen dose, probably due to the lack of an effective H V-specific CD4+ T-cell response. If this CD4+ T-cell response is lost due to viral induced anergy, rather than clonal deletion, such responses may be generated by interruptions in antiretroviral treatment, and/or therapeutic immunization in chronically infected patients. A strong immune response stimulated at low-antigen dose early during viral rebound may be critical in preventing accumulation of toxic viral products that might inhibit effective CD4+ T-cell responses., Conclusion: Immune control of HIV infection is a realistic goal. Understanding both the basic immune mechanisms of in vivo viral replication and identifying practical therapeutic regimens to activate HIV CD4+ and CD8+ T-cell responses may allow the development of efficient immune control of HIV replication in chronically infected patients.

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors have dramatically improved treatment options for HIV infection, but frequent dosing may impact adherence to highly active antiretroviral treatment regimens (HAART). Previous studies demonstrated that combined therapy with ritonavir and saquinavir allows a decrease in frequency of saquinavir dosing to twice daily. In this study, we evaluated the safety and pharmacokinetics of combining once-daily doses of the soft-gel capsule (SGC) formulation of saquinavir (saquinavir-SGC) and minidose ritonavir. Forty-four healthy HIV-negative volunteers were randomized into groups receiving once-daily doses of saquinavir-SGC (1,200 to 1,800 mg) plus ritonavir (100 to 200 mg) or a control group receiving only saquinavir-SGC (1,200 mg) three times daily. Saquinavir-SGC alone and saquinavir-SGC-ritonavir combinations were generally well tolerated, and there were no safety concerns. Addition of ritonavir (100 mg) to saquinavir-SGC (1,200 to 1,800 mg/day) increased the area under the concentration-time curve (AUC) for saquinavir severalfold, and the intersubject peak concentration in plasma and AUC variability were reduced compared to those achieved with saquinavir-SGC alone (3,600 mg/day), while trough saquinavir levels (24 h post-dose) were substantially higher than the 90% inhibitory concentration calculated from HIV-1 clinical isolates. Neither increasing the saquinavir-SGC dose to higher than 1,600 mg nor increasing ritonavir from 100 to 200 mg appeared to further enhance the AUC. These results suggest that an all once-daily HAART regimen, utilizing saquinavir-SGC plus a more tolerable low dose of ritonavir, may be feasible. Studies of once-daily saquinavir-SGC (1,600 mg) in combination with ritonavir (100 mg) in HIV-infected patients are underway.

Because there is limited information about suppression of virus loads (determined by current "ultrasensitive" assays) in patients receiving nucleoside reverse-transcriptase inhibitors (NRTIs) alone, we reviewed our experience in clinical practice with patients who had virus loads of <25 copies/mL after >1 year of treatment with dual NRTIs.

Background: Clinical and virologic consequences of temporary interruption of HIV therapy are incompletely understood., Objective: To describe a febrile illness that was consistent with the acute HIV syndrome and occurred after interruption of antiretroviral therapy., Design: Case report., Setting: University clinic., Patient: HIV-infected man., Measurements: Plasma viral load, lymphocyte subsets, diagnostic evaluation (including cultures and serologic tests), and analysis of lymph node tissue., Results: The patient began antiretroviral therapy 3 months after initial HIV exposure and had sustained viral suppression, except during a brief scheduled treatment interruption. One hundred sixty-nine days after resuming therapy, the patient discontinued it again immediately following an influenza vaccination. Eleven days later, he presented with a febrile mononucleosis-like syndrome associated with dramatic shifts in plasma HIV RNA level (<50 to >1 000 000 copies/mL) and CD4 cell count (0.743 x 10(9) cells/L to 0.086 x 10(9) cells/L). Evaluation for alternative causes of fever was unrevealing. Symptoms resolved rapidly with resumption of HIV therapy., Conclusion: Therapeutic interruption may be associated with profound viral rebound and recurrence of the acute HIV syndrome.

HIV infection leads to loss of CD4 T cells and development of AIDS in most individuals without treatment. While disease progression during HIV infection correlates with the plasma viral load, much less is known about the levels of HIV vDNA. This paper describes the development and validation of a sensitive, quantitative PCR assay for the assessment of HIV vDNA. The system uses novel single tube, multiply competitive PCR technology, which allows five-point competitor competition in a single PCR reaction. The reproducibility and performance characteristics of the assay are extensively studied, which indicate that the system performs well in high DNA backgrounds. Using this assay system on a cohort of protease naïve patients, HIV vDNA was assessed from PBMCs over an average follow-up period of 5 years. The data indicate that the HIV vDNA pool does not appreciably accumulate over the follow-up period, with many of the patients followed for up to 8 years. A reliable, quantitative assessment of vDNA pools will allow a better understanding of the dynamics of HIV pathogenesis.

Bone marrow cultures and biopsy specimens are commonly obtained to rule out disseminated infections, especially in persons with the acquired immunodeficiency syndrome (AIDS) and cytopenias. Using culture as the gold standard, we reviewed 130 consecutive bone marrow cores obtained from 114 AIDS patients along with results of concurrent blood and/or bone marrow aspirate cultures to determine the usefulness of histologic examination for diagnosis of mycobacterial and fungal infections. We also compared the ability of Ziehl-Neelsen, auramine-rhodamine (AR), polyclonal antibody to Mycobacterium bovis (Ab), and Gomori's methenamine silver staining to detect infections. Twenty-seven patients had mycobacterial infection (25 Mycobacterium avium-intracellulare complex cases and two Mycobacterium tuberculosis cases) detected by blood and/or bone marrow cultures. The maximum sensitivity of histology was 50% when the auramine-rhodamine stain and the polyclonal antibody to M bovis were used in combination. The single best stain was auramine-rhodamine, with a sensitivity of 44%, followed by the polyclonal antibody to M bovis (35%). Granulomas were observed in nine cases of mycobacterial infection and did not correlate with the presence of stainable organisms. Of seven patients with positive fungal cultures of bone marrow, four had granulomas and a positive Gomori's methenamine silver stain, one had only a positive stain, and two had neither granulomas nor a diagnostic stain. Overall, granulomas were not sensitive for the detection of infections when culture-proven mycobacterial and fungal cases were evaluated together. We conclude that bone marrow examination has a limited value in the routine evaluation of common opportunistic infections in AIDS patients and recommend that less-invasive tests, such as blood cultures, be obtained initially in most circumstances.