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People living with HIV-1 and HTLV-2 concomitantly show slower CD4 + T cell depletion and AIDS progression, more frequency of the natural control of HIV-1, and lower mortality rates. A similar beneficial effect of this infection has been reported on HCV coinfection reducing transaminases, increasing the spontaneous clearance of HCV infection and delaying the development of hepatic fibrosis. Given the critical role of CD8 + T cells in controlling HIV-1 infection, we analysed the role of CD8 + T cell-mediated cytotoxic activity in coinfected individuals living with HIV-1. One hundred and twenty-eight individuals living with HIV-1 in four groups were studied: two groups with HTLV-2 infection, including individuals with HCV infection (N = 41) and with a sustained virological response (SVR) after HCV treatment (N = 25); and two groups without HTLV-2 infection, including individuals with HCV infection (N = 25) and with a sustained virological response after treatment (N = 37). We found that CD8 + T cell-mediated HIV-1 inhibition in vitro was higher in individuals with HTLV-2. This inhibition activity was associated with a higher frequency of effector memory CD8 + T cells, higher levels of granzyme A and granzyme B cytolytic enzymes, and perforin. Hence, cellular and soluble cytolytic factors may contribute to the lower HIV-1 pre-ART viral load and the HIV-1 proviral load during ART therapy associated with HTLV-2 infection. Herein, we confirmed and expanded previous findings on the role of HTLV-2 in the beneficial effect on the pathogenesis of HIV-1 in coinfected individuals.

The CD4/CD8 ratio is an indirect marker of immune activation, immune senescence, and inflammation in HIV infection. We performed a prospective study of the CD4/CD8 ratio evolution in 245 virally-suppressed (median, 55 months) HIV-infected patients (29% females) who had switched to four dual antiretroviral regimens. At baseline, the median CD4/CD8 ratio was 0.71 (interquartile range, IQR, 0.46-0.97), associated with duration of HIV infection, nadir CD4+ cell count, and AIDS diagnosis. It was lower in the case of hepatitis C virus coinfection and cardiovascular disease (p = 0.09), but the ratio was higher in patients with chronic kidney disease, proteinuria, or osteoporosis. At 48 weeks, the median CD4/CD8 ratio increased by 3% (+0.02; IQR, -0.07, +0.09; p = 0.07); greater improvement was observed in patients with lower baseline ratios and previous AIDS diagnosis. The slope of increase was slower in patients with the highest baseline values. Also, there were no differences in the CD4/CD8 ratio increase according to type of dual regimen, after adjusting for baseline and HIV-related values. In conclusion, CD4/CD8 ratio increase is observed during suppressive dual regimens, and its extent is related to baseline values and previous HIV-related factors. Longer duration on antiretroviral therapy and drug toxicity could affect the evolution of this marker in the presence of comorbidities.

In this issue of EBioMedicine, Ruggiero and colleagues describe immune activation biomarkers associated with the size of the HIV reservoir in a carefully designed cross-sectional study. The cohort consists of a homogeneous sample of HIV-1-infected patients with long-term plasma HIV-1 RNA suppression under antiretroviral treatment (ART). It is crucial to explore the potential utility of biomarkers that are easier (less labor intensive, less expensive) to measure than integrated HIV DNA load, in order to quickly and accurately quantify cellular reservoirs of HIV.

Background: HIV-1-infected individuals progressively loss CD4(+) T cells leading to immunosuppression and raising the risk of opportunistic infections. CD8(+) T-cells play an important role in the immune response against virus infections through their TCR., Objective: To evaluate the CD8-TCR repertoire and immunologic markers in HIV-1-infected patients., Study Design: Ten chronic HIV-1-infected individuals on prolonged effective antiretroviral treatment (ART) were analyzed at baseline (before treatment interruption), after at least one year of treatment interruption (TI) and after at least one year from ART resume (TR). Twenty-four TCR-Vβ gene families were analyzed by a modified CDR3 spectratyping method in isolated CD8(+) T-cells. Immune activation, exhaustion and subpopulation markers were analyzed by flow cytometry., Results: Expansion of Vβ10, Vβ14 and Vβ15 families, associated with low cell activation and stable exhaustion markers, were found at TI. Moreover, an increment of effector memory cells was found. Besides, depletion of Vβ20, Vβ28, and Vβ29 families, associated with an increase in cell activation and exhaustion markers, at TI were also found. These alterations seemed to be more pronounced in patients who had longer time from diagnosis. ART seemed to restore altered CD8(+) T-cell repertoire and most of the immunologic markers., Conclusions: During TI (that was more pronounced in patients with longer HIV-1 infection) it was observed the expansion of Vβ families correlated with decreased cell activation, while Vβ families correlated with cell activation and exhaustion were depleted. These specific repertoire alterations reverted after ART resume., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Microbial translocation (MT) has been proposed as one of the triggering mechanisms of persistent immune activation associated to HIV-1 infection. Our objectives were to determine the correlation between different measurements of MT in suppressed HIV-1-infected individuals and to evaluate its correlation with immune activation., Methods: Eighteen suppressed HIV-1-infected patients with CD4+ T-cell count above 350 cells per cubic millimeter and undetectable plasma viral load, included in antiretroviral treatment intensification clinical trials, were evaluated. Samples obtained at baseline and at established time points during the trials were analyzed. Lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), and bacterial 16S ribosomal DNA (16S rDNA), and markers of immune activation were determined., Results: We analyzed 126 plasma samples from the 18 patients. LPS significantly correlated with sCD14 (P < 0.001, r = 0.407) and LBP (P = 0.042, r = 0.260). Also, a significant correlation was found between sCD14 and LBP (P = 0.009, r = 0.325) but not between bacterial 16S rDNA and LPS, sCD14, or LBP (P = 0.346, P = 0.405, and P = 0.644). On the other hand, no significant correlation was found between LPS, sCD14, or LBP and CD4 (P = 0.418, P = 0.619, and P = 0.728) or CD8 T-cell activation (P = 0.352, P = 0.275, and P = 0.124). Bacterial 16S rDNA correlated with activated CD4 T cells (P = 0.005, r = 0.104) but not with activated CD8 T cells (P = 0.171)., Conclusions: There is a good correlation in the quantification of LPS, sCD14, and LBP levels, but not with bacterial 16S rDNA, as measurements of MT. We are unable to ensure that MT directly triggers T-cell immune activation at least among these patients with relatively good immune recovery and under treatment intensification.

Objective: Antiretroviral therapy (ART) intensification has been shown to reduce the reservoir of latently infected CD4 T cells. However, it is currently unknown whether this effect is maintained after discontinuation of the intensifying drug., Design: The effect of ART intensification during 48 weeks with maraviroc or raltegravir in chronically HIV-1-infected patients was assessed in two previous clinical trials. In this study, we analysed this effect at week 24 after discontinuation of the intensifying drugs, at baseline and 48 weeks of intensification., Methods: We measured the latently infected memory CD4 T cells carrying replication-competent virus, 2-long terminal repeat (2-LTR) circles and CD4/CD8 T cells activation., Results: Fifteen patients were evaluated. After 48 weeks of intensification, HIV-1 reservoir size significantly decreased from 1.1 to 0.0 infectious units per million (IUPM) (P=0.004). After 24 weeks of drug discontinuation, the median size of the reservoir was still significantly lower than at baseline (P=0.008). 2-LTRs were undetectable in all individuals at baseline and after 48 weeks of intensification, continuing undetectable in all patients except two at week 24 after discontinuation (P=0.1). CD4 and CD8 T-cell activation significantly decreased at 48 weeks after intensification, without further increase after discontinuation., Conclusion: The effects of ART intensification with maraviroc or raltegravir persist at least 24 weeks after discontinuation of the drug. In a global strategy, ART intensification should be considered as part of a combination approach to achieve a functional cure or HIV eradication.

Objectives: The stability of the reservoir of latently infected memory CD4 T-cells may be associated with continuous replenishment from residual HIV-1, not completely eliminated by otherwise successful antiretroviral therapy (ART). Treatment intensification could help to control residual virus and to modify the latent reservoir. The objective of this work is to assess the effect of intensifying therapy with raltegravir on the HIV-1 cell reservoir., Design: A pilot open-label phase-II clinical trial was performed to analyze ART intensification with raltegravir after 48 weeks in chronically HIV-1-infected patients on stable ART., Methods: We measured the number of latently infected memory CD4 T cells, residual viremia, 2-long terminal repeat circles, CD4/CD8 T-cell activation, lymphocyte subpopulations, gut homing receptor, and bacterial translocation., Results: A significant decay of HIV-1 latent reservoir was observed after intensification in the nine patients included (P = 0.021). No variation was found in either residual viremia or 2-long terminal repeat circles, whereas CD8 T-cell activation decreased at week 36 (P = 0.028). No differences were found in naive T-cell or effector memory cell counts, and the frequencies of gut homing receptor on activated or effector memory CD8 T cells. Bacterial translocation was stable, with the exception of a late decrease in lipopolysaccharide levels., Conclusions: In this pilot noncomparative trial, treatment intensification with raltegravir significantly decreased the latent cellular HIV-1 reservoir and CD8 T-cell activation. Despite the limitations inherent to trial design, our results suggest that ART intensification should be considered as an adjuvant strategy to eradicate HIV-1 infection.

Background: Most of the non-B HIV-1 subtypes are predominant in Sub-Saharan Africa and India although they have been found worldwide. In the last decade, immigration from these areas has increased considerably in Spain. The objective of this study was to evaluate the prevalence of non-B subtypes circulating in a cohort of HIV-1-infected immigrants in Seville, Southern Spain and to identify drug resistance-associated mutations., Methods: Complete protease and first 220 codons of the reverse transcriptase coding regions were amplified and sequenced by population sequencing. HIV-1 subtypes were determined using Stanford University Drug Resistance Database, and phylogenetic analysis was performed comparing multiple reported sequences. Drug resistance mutations were defined according to the International AIDS Society-USA., Results: From 2000 to 2010 a total of 1,089 newly diagnosed HIV-1-infected patients were enrolled in our cohort. Of these, 121 were immigrants, of which 98 had ethical approval and informed consent to include in our study. Twenty-nine immigrants (29/98, 29.6%) were infected with non-B subtypes, of which 15/29 (51.7%) were CRF02-AG, mostly from Sub-Saharan Africa, and 2/29 (6.9%) were CRF01-AE from Eastern Europe. A, C, F, J and G subtypes from Eastern Europe, Central-South America and Sub-Saharan Africa were also present. Some others harboured recombinant forms CRF02-AG/CRF01-AE, CRF2-AG/G and F/B, B/C, and K/G, in PR and RT-coding regions. Patients infected with non-B subtypes showed a high frequency of minor protease inhibitor resistance mutations, M36I, L63P, and K20R/I. Only one patient, CRF02&#95;AG, showed major resistance mutation L90M. Major RT inhibitor resistance mutations K70R and A98G were present in one patient with subtype G, L100I in one patient with CRF01&#95;AE, and K103N in another patient with CRF01&#95;AE. Three patients had other mutations such as V118I, E138A and V90I., Conclusions: The circulation of non-B subtypes has significantly increased in Southern Spain during the last decade, with 29.6% prevalence, in association with demographic changes among immigrants. This could be an issue in the treatment and management of these patients. Resistance mutations have been detected in these patients with a prevalence of 7% among treatment-naïve patients compared with the 21% detected among patients under HAART or during treatment interruption.

Objective: The primary objective was to assess the effect of MVC intensification on latently infected CD4(+) T cells in chronically HIV-1-infected patients receiving antiretroviral therapy., Methods: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation., Results: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4(+) or CD8(+) counts, although a significant decrease was found in the proportion of HLA-DR(+)/CD38(+) CD4(+) and CD8(+) T-cells. LPS and sCD14 levels increased., Conclusions: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results., Trial Registration: ClinicalTrials.gov NCT00795444.

Immunovirologic parameters of 24 heavily antiretroviral drug-pretreated patients with prolonged virologic treatment failure under highly active antiretroviral therapy, and who harbored highly resistant human immunodeficiency virus (HIV) isolates, were studied in this retrospective cross-sectional study. Most of the patients were injecting drug users (71%) and male (88%). All patients were studied for CD4(+) cell count, HIV viral load, resistance mutations, and viral phenotype. The patients showed a high accumulation of resistance-associated mutations, their CD4(+) cell count and viral load directly correlated with their respective values at initiation of therapy, and the presence of K103N was inversely associated with lower viral load. On the other hand, patients with K103N had the same level of CD4(+) cell count compared with patients without this mutation. Among the patients, a majority with a specific viral phenotype was not present. Rather, a dual-tropic virus was found most frequently, suggesting a preferential suppression of X4-specific strains and less cytopathogenicity during antiretroviral therapy and a greater proportion of R5X4 viruses due to an adaptation to that pressure.

Multiple nucleic acid-based techniques (NAT) have been implemented for testing blood and plasma donors for HIV-1 RNA which may be detected at an earlier stage of infection when HIV antigen or antibody is absent or below the limit of detection of current assays. The available NAT assays are based on different technologies. In order to evaluate the performance of nucleic acid-based techniques (NAT assays) and to allow accurate comparisons of results from different assays, it is essential to have well characterized specimens with known copy numbers as a standard. For this purpose, a comprehensive study was conducted to develop two HIV-1 RNA reference panels. The first (Panel 1) was prepared using a single specimen from the HIV-1 group M subtype B and consists of panel members with a wide range of HIV-1 RNA copy numbers. Panel 2 consists of 26 members representing HIV-1 group M subtypes A, C, D, E, F, G and groups O and N. For accurate determination of HIV-1 RNA copy numbers of each member of Panel 2, they were analyzed using various testing platforms/technologies available through the cooperation of five independent laboratories participating in the study. A consensus value for HIV RNA copy number was assigned to each member of Panel 2 based on statistical analysis of the data provided by the participants. Both panels could serve as reference panels to be used by manufacturers of HIV NAT tests to evaluate the sensitivity limits of their assays.

One of the strategies that has been investigated to reduce antiretroviral treatment toxicity in patients infected with human immunodeficiency virus (HIV) is structured treatment interruption (STI). Our aim was to analyze early viral and immune dynamics after interruption of highly active antiretroviral therapy (HAART) and to determine whether thymic function-related markers play a role in preventing CD4 count decline caused by increased viral replication. This was a prospective study of an open cohort of 47 HIV-infected patients with a median 969 CD4 count and prolonged viral suppression. They were followed every 4 weeks though week 24. Thymic volume and TREC level were analyzed at baseline. Increased thymic volume was associated with higher plasma viral load and greater CD4 count decline early after interruption. Three virologic patterns were observed: rapid/high (RH), delayed/high (DH), and low/slow (LS) viral replication. RH correlated with higher thymic volume at baseline and with higher CD4 count decline at week 4. Patients with greater thymic volume was associated with an immune and virologic impairment only early after interruption, probably because of infection of the increased number of available target cells. As the long-term consequences of these observations are unknown, the safety of treatment interruption must be further studied.

Once highly active antiretroviral therapy (HAART) fails to suppress HIV replication and resistant viruses emerge, it is difficult to find a salvage regimen since cross-resistance is high among the available classes of antiretroviral drugs. In this retrospective analysis, genotypic resistance profiles were analysed in 24 patients who switched treatment to abacavir (ABV), efavirenz (EFV), and either a NRTI or a PI at baseline and after 24 weeks of treatment. At baseline, 71% of patients harboured at least one resistance mutation in the protease gene. In the RT gene, 87.5% of the patients showed nucleoside analogue resistance mutations, and an equal 87.5% showed resistance mutations to non-nucleoside analogues. After 24 weeks of treatment, only mutations to nucleoside analogues raised in 95.8% of the patients, while resistance mutations to the other drug classes remained constant. Substitutions conferring cross-resistance within each drug family were very common among this treatment-experienced population. These data also indicate that salvage therapy is likely to remain one of the most important issues in the treatment of HIV infections.

Objective: To assess the durability of the undetectability of HIV plasma viraemia (pV) and to determine the factors associated with virological rebound (VR) in HIV-infected adults on protease inhibitor (PI)-sparing highly active antiretroviral therapy (HAART). The development of resistance mutations during virologically successful therapy and VR was also analysed., Materials and Methods: One hundred and twenty-six HIV-infected adults on PI-sparing HAART were prospectively followed from April 1998 to December 2002: Group 1, naive for antiretroviral drugs (n = 26); Group 2, previously PI-HAART-exposed patients (n = 19); Group 3, previously exposed to suboptimal therapy (n = 81). Genotypic resistance tests on peripheral blood mononuclear cells or on plasma RNA (when feasible) were carried out when undetectable HIV pV was demonstrated for at least 48 weeks. Additionally, patients showing a therapy adherence >95% developing VR were also tested at rebound, at simplification and during previous suboptimal therapy exposure., Results: The median follow-up time was 630 [329-903] days. VR was considered as two consecutive pV levels >50 copies/mL. Twenty-two (17.5%) patients developed VR. Only therapy adherence <95% was independently associated with VR (adjusted hazard ratio: 8.42; 95% CI: 3.33-21.27). Twenty (40%) of the 50 patients with pV < 50 copies/mL for at least 48 weeks showed at least one thymidine-associated mutation (TAM) but none had NNRTI-resistance mutations. Ten (83.3%) of 12 available adherent patients showing VR harboured NNRTI-resistance-associated mutations; 50% of them were considered as wild-type strains at simplification time. However, the TAM number and resistance mutations profile found on suboptimal exposure were very similar to those found at VR on simplification therapy., Conclusions: PI-sparing HAART allows maintenance of successful long-term control of HIV replication, adherence to therapy being the main factor associated with VR. However, a small proportion of patients on simplification regimen may develop VR regardless of therapy compliance. VR on PI-sparing HAART is characterized by the emergence of NNRTI cross-resistance mutations. Finally, TAMs 'archived' during previous suboptimal exposures are partially involved in subsequent VR on simplification HAART.

Human immunodeficiency virus type 1 group O strains have been described as highly divergent, compared with the majority of the viruses classified in group M. To study the diversity and genetic characteristics of group O, we have sequenced the accessory genes of 7 isolates. Analysis of the deduced amino acid sequences for Vif, Vpr, Tat, Vpu, and Rev indicate that most of the functional domains of these proteins, as described for group M viruses, are highly conserved and retained among all the group O strains we have characterized. The only difference concerns the Vif phosphorylation sites, which are absent in all of the group O isolated we have sequence with the exception of two isolates in which only one phosphorylation site was conserved. These sites, present in nearly all of the group M isolates, play a critical role in the regulation of viral replication and infectivity. As described for group M isolates, the vpu gene is the one with the highest diversity among group O viruses. Phylogenetic analysis of these sequences suggests that group O viruses could be differentiated into at least four different clusters.

Background The human T-lymphotropic virus type I (HTLV-I) has been implicated in the genesis of tropical spastic paraparesis (TSP), adult T-cell lymphoma (ATL), and some cases of uveitis, subacute arthropathies, chronic dermatitis and lymphocytic alveolitis. The virus is endemic in some areas of the Caribbean basin, Japan, subSaharan Africa, Central and South America, Middle East and Melanesia. Given that HTLV-I is transmitted through similar ways to HIV, screening in blood donors is recommended in some countries. Material and Methods The clinical, epidemiological and virological characteristics of 27 patients with HTLV-I infection were identified in Spain up to September 1995. Results Eighteen cases were Spanish natives and 9 were immigrants from endemic areas. Fifteen were male and 12 were female. The majority (12/18; 66.7%) of subjects born in Spain had resided in endemic areas or had had sexual partners from these regions. Four patients had TSP, three had ATL and one developed lymphomatous granulomatosis and T-cell lymphoma. The remaining HTLV-I subjects were asymptomatic at the time of diagnosis. Four cases were identified from screening of blood donors. Conclusion HTLV-I is present in Spain, affecting natives and, less frequently, immigrants from endemic areas. Both neurological and lymphoproliferative diseases have been recognized in a quarter of patients. [ABSTRACT FROM PUBLISHER]

The incidence of classical Hodgkin lymphoma (cHL) in the HIV-1 setting has increased 5–25-fold compared to that observed in the general population. This study aimed to determine whether selected micro RNAs (miRs) and other soluble biomarkers and cellular subsets are dysregulated in cHL and could be used as biomarkers. This was a retrospective and longitudinal matched case-control study of 111 Caucasian, HIV-1-infected adult individuals, including 37 individuals with cHL and 74 with no type of cancer. Immunovirological data, plasma exosome-derived miR-16, miR-20a, miR-21, miR-221, miR-223, miR-106a, miR-185, miR-23, miR-30d, miR-222, miR-146a and miR-324, plasma IL-6, sCD14, sCD27, sCD30, sIL-2R, TNFR1, and cell phenotyping of T and B lymphocytes and natural killer (NK) cells were analyzed. Before cHL diagnosis, miR-20a, miR-21, and sCD30 were higher in cHL (p = 0.008, p = 0.009 and p = 0.042, respectively), while miR-16 was down-regulated (p = 0.040). miR-20a and miR-21 were independently associated with cHL (p = 0.049 and p = 0.035, respectively). The combination of miR-20a and miR-21 showed a good AUC value of 0.832 with a moderate likelihood ratio positive (LR+) value of 5.6 and a slight likelihood ratio negative (LR−) value of 0.23. At cHL diagnosis, miR-20a, miR-21 and miR-324 were overexpressed in cHL (p = 0.005, p = 0.024, and p = 0.001, respectively), while miR-223, miR-16, miR-185 and miR-106a were down regulated (p = 0.042, p = 0.007, p = 0.006, and p = 0.002, respectively). In addition, sCD14, sCD27, sCD30 and IL2R levels were higher in these individuals (p = 0.038, p = 0.010, p = 0.030, p = 0.006, respectively). miR-20a was independently associated with cHL (p = 0.011). The diagnostic value of miR-20a showed good AUC value of 0.754 (p = 0.074) with a slight LR+ value of 2 and a slight LR− of 0.25. After chemotherapy, miR-20a was higher in those individuals who had an adverse outcome (p < 0.001), while sCD14 and sCD30 were higher (p < 0.001). A specific signature of miRs and cytokines associated with a subsequent cHL diagnosis was found in this study, especially miR-20a and miR-21. Also, another biomarker signature was found at cHL diagnosis, with a relevant discriminant disease value for miR-20a. Of note, miR-20a expression was higher in those individuals who had an adverse clinical outcome after chemotherapy. [ABSTRACT FROM AUTHOR]