Search

Purpose of Review: This review summarizes recent research literature relevant to mucosal immunity and acute/early HIV infection., Recent Findings: Recent findings include new insights on the HIV transmission "bottleneck" at mucosal surfaces, the impact of acute HIV on germinal centers and mucosal B-cell function, the expression of cytotoxic effector molecules by mucosal CD8+ T-cells, and an enhanced understanding of the impact of acute HIV on innate cell-mediated defenses including mucosa-associated invariant T-cells invarant natural killer T-cells and natural killer cells., Summary: Now more than 40 years since the beginning of the HIV/AIDS pandemic, extensive research has elucidated the dynamics of HIV replication and the corresponding host response. However, the vast majority of HIV-related immunopathogenesis studies have focused on innate and adaptive immune responses in peripheral blood. Mucosal tissues serve as the primary portals of entry for HIV and house the majority of the body's lymphocytes. Innate and adaptive immune responses in mucosal tissues are of particular relevance during the acute phase of HIV disease, as successful defenses can both limit viral dissemination within the host and prevent transmission to a new host, yet until recently these responses were poorly understood., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: This review summarizes our current understanding of HIV-1-specific T-cell responses in mucosal tissues, emphasizing recent work and specifically highlighting papers published over the past 18 months., Recent Findings: Recent work has improved the standardization of tissue sampling approaches and provided new insights on the abundance, phenotype and distribution of HIV-1-specific T-cell populations in mucosal tissues. In addition, it has recently been established that some lymphocytes exist in tissues as "permanent resident" memory cells that differ from their counterparts in blood., Summary: HIV-1-specific T-cell responses have been extensively characterized; however, the vast majority of reports have focused on T-cells isolated from peripheral blood. Mucosal tissues of the genitourinary and gastrointestinal tracts serve as the primary sites of HIV-1 transmission, and provide "front line" barrier defenses against HIV-1 and other pathogens. In addition, the gastrointestinal tract remains a significant viral reservoir throughout the chronic phase of infection. Tissue-based immune responses may be critical in fighting infection, and understanding these defenses may lead to improved vaccines and immunotherapeutic strategies.

Objective: Elite controllers are a rare subset of HIV-1-infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (<20-50 copies/ml) in the absence of antiretroviral therapy. Here, we examine to what extent elite controllers also control infection of the central nervous system (CNS)., Design: We analysed paired cerebrospinal fluid (CSF) and plasma samples using a highly sensitive assay for HIV-1 RNA quantification., Methods: We analysed 28 CSF samples and 27 concurrent plasma samples from 14 elite controllers with the highly sensitive single-copy assay (SCA) that allows for HIV-1 RNA quantification down to less than one copy of HIV-1 RNA per millilitre., Results: Three samples were excluded because of internal standard failure. HIV-1 RNA was detected in only five of 26 CSF samples compared with 14 of 26 plasma samples (P = 0.02), with a median of 0.2 (range, 0.1-6) copies/ml in CSF compared with 0.8 (range, 0.1-189 copies/ml) in plasma (P < 0.0001)., Conclusion: HIV-1 RNA could not be detected in CSF in most elite controllers using the highly sensitive SCA, and when detected, it was at significantly lower frequencies and concentrations than in plasma. Elite controllers thus control HIV-1 in the CNS very well. Whether the infrequent and small amounts of HIV-1 RNA in the CSF reflect production from a local reservoir or virion exchange between the blood and the CSF is uncertain.

Objective: The objective of this study was to assess the effects of HAART initiation on CD4(+) T-cell repopulation and T-cell immune activation in rectal and duodenal mucosa., Design: The effects of HAART on the gastrointestinal tract remain controversial, and studies have reached different conclusions regarding its effectiveness at restoring mucosal CD4(+) T cells depending upon time of initiation, duration of treatment and gastrointestinal tract region studied., Methods: We obtained blood, rectal biopsies and duodenal biopsies from 14 chronically infected individuals at baseline and at 4-9 months post-HAART initiation. We examined CD4(+) T-cell frequencies in blood, rectum and duodenum at both time points, and performed a detailed assessment of CD4(+) T-cell phenotype, immune activation marker expression and HIV-specific CD8(+) T-cell responses in blood and rectal mucosa., Results: CD4(+) T-cell percentages increased significantly in blood, rectal and duodenal mucosa after 4-9 months of HAART (P = 0.02, 0.0005, 0.0002), but remained lower than in uninfected controls. HIV-specific CD8(+) T-cell responses in blood and rectal mucosa declined following HAART initiation (P = 0.0015, 0.021). CD8(+) T-cell coexpression of CD38 and HLA-DR in blood and mucosa, as well as plasma sCD14, declined significantly. CD28 expression on blood and mucosal CD8(+) T cells increased, whereas programmed death receptor-1 expression on blood HIV-specific CD4(+) and CD8(+) T cells decreased., Conclusion: Within the first months of HAART, limited CD4(+) T-cell reconstitution occurs in small and large intestinal mucosa. Nevertheless, decreased immune activation and increased CD28 expression suggest rapid immunological benefits of HAART despite incomplete CD4(+) T-cell reconstitution.

Objective: To determine whether the ability of primary myeloid dendritic cells (mDCs) to induce regulatory T cells (Treg) is affected by chronic simian immunodeficiency virus (SIV) infection., Design: Modulation of dendritic cell activity with the aim of influencing Treg frequency may lead to new treatment options for HIV and strategies for vaccine development., Methods: Eleven chronically infected SIV(+) Rhesus macaques were compared with four uninfected animals. Immature and mature mDCs were isolated from mesenteric lymph nodes and spleen by cell sorting and cultured with purified autologous non-Treg (CD4(+)CD25(-) T cells). CD25 and FOXP3 up-regulation was used to assess Treg induction., Results: The frequency of splenic mDC and plasmacytoid dendritic cell was lower in infected animals than in uninfected animals; their frequency in the mesenteric lymph nodes was not significantly altered, but the percentage of mature mDCs was increased in the mesenteric lymph nodes of infected animals. Mature splenic or mesenteric mDCs from infected animals were significantly more efficient at inducing Treg than mDCs from uninfected animals. Mature mDCs from infected macaques induced more conversion than immature mDCs. Splenic mDCs were as efficient as mesenteric mDCs in this context and CD103 expression by mDCs did not appear to influence the level of conversion., Conclusions: Tissue mDCs from SIV-infected animals exhibit an enhanced capability to induce Treg and may contribute to the accumulation of Treg in lymphoid tissues during progressive infection. The activation status of dendritic cell impacts this process but the capacity to induce Treg was not restricted to mucosal dendritic cells in infected animals.

Purpose of Review: The phenomenon of long-term nonprogression in HIV infection has been recognized for some time, and the ability of rare individuals, designated 'elite controllers', to control HIV in the absence of therapy is the focus of numerous ongoing studies. This review focuses on studies of HIV-specific immune responses in mucosal tissues as a potential correlate of immune control, with an emphasis on recently published work., Recent Findings: Genetic studies have implicated a role for elements localized to the major histocompatibility complex (MHC) on chromosome 6 in the immune control of HIV infection. In parallel, functional studies have strongly implicated MHC class I-restricted, CD8+ T-cell responses as a major contributor to elite control. In addition, the localization of HIV-specific CD8+ and CD4+ T cells with respect to the major sites of virus replication in the body may be critical in determining clinical outcome., Summary: Recent findings suggest that MHC class I-restricted, CD8+ T cells are a major component of immune control in 'elite controllers'. In addition, the presence of these effector cells at or near critical viral reservoirs, such as mucosal tissues, may be critical in determining their effectiveness at limiting viral replication and dissemination.

Purpose of Review: This review summarizes research literature regarding mucosal immunity to HIV and simian immunodeficiency virus (SIV), with an emphasis on work published within the past 18 months., Recent Findings: Notable recent studies have focused on the pivotal events occurring within mucosal tissues during acute HIV/SIV infection that serve to establish a balance between detrimental immune activation and beneficial adaptive responses. In cervicovaginal mucosa, an early inflammatory response leads to recruitment of susceptible target cells. At this acute stage, the in-vivo ratio between CD8 effector cells and infected CD4 T-cells may be critical for limiting viral dissemination. Acute infection is also accompanied by loss of germinal center architecture and T/B cell apoptosis in Peyer's patches of the gastrointestinal tract. During chronic infection, mucosal CD8 T-cells may play a role in immune control, as suggested by studies of elite controllers., Summary: Mucosal tissues serve as the major portal of entry for HIV, and house a majority of the body's lymphocytes, including CD4 T-cells that are targets for infection. Recent studies have focused renewed attention on events occurring immediately after transmission, and underscore the concept that the balance between inflammation and protective immunity is established by host responses in mucosal tissues.

Purpose of Review: This review summarizes recent literature in the field of mucosal immunology as it applies to HIV transmission and pathogenesis., Recent Findings: Pertinent recent findings include elucidation of the role of mucosal antigen-presenting cells and retinoic acid in imprinting a gut-homing phenotype on antigen-specific T and B cells, and the identification of Th17 and T regulatory cells as key modulators of the balance between tolerance and inflammation in mucosal tissues., Summary: Mucosal surfaces of the body serve as the major portal of entry for HIV. These tissues also house a majority of the body's lymphocytes, including the CD4 T-cells that are the major cellular target for HIV infection. Elucidating mucosal immune responses is critical to our understanding of the host-pathogen relationship for two reasons: first, mucosal barriers are defended by a range of innate and adaptive defenses that might be exploited to develop effective vaccines or microbicides; second, adaptive immune responses in mucosal lymphoid tissues might serve to limit viral replication, decreasing the host's viral burden as well as reducing the likelihood of sexual transmission to a naïve host.

Objective: To utilize the potent antigen-presenting capacity of mature dendritic cells (MDC) in order to develop a rapid, sensitive method for quantifying antigen-specific CD8 T cells present at low frequency in peripheral blood., Design: Peripheral blood mononuclear cells (PBMC) were obtained from seven HIV-1-positive individuals with low to moderate CD8 T cell responses, including five on highly active antiretroviral therapy (HAART). IFN-gamma ELISPOT assays were performed using either monocytes or MDC to present antigens expressed by recombinant vaccinia viruses (r-VV)., Methods: Peripheral blood-derived monocytes were cultured for 5-6 days in the presence of IL-4 and granulocyte macrophage colony-stimulating factor, then matured in monocyte-conditioned medium. MDC were infected with r-VV and co-cultured in an ELISPOT assay with autologous monocyte-depleted PBMC., Results: Relative to autologous monocytes, MDC amplified detection of antigen-specific CD8 T cells by 2-30-fold in response to antigens from HIV-1, Epstein-Barr virus and cytomegalovirus. Furthermore, antigenic specificities were revealed that had not been detected using standard ELISPOT of PBMC., Conclusion: This assay will prove useful for the detection of memory T cells present at low frequency, and may be of interest for identifying subdominant cytotoxic T lymphocyte epitopes. This method may have broad applications for the detection of antiviral CD8 T cell responses in patient populations in whom such responses have been difficult to detect, including HIV-1-seropositive individuals with advanced disease or undergoing HAART.

Objective: To characterize HIV-1 specific cellular immune responses at mucosal surfaces using a rapid, sensitive enzyme-linked immuno-spot (ELISPOT) technique., Design: Cervicovaginal mononuclear cells obtained from cytobrush and cervicovaginal lavage were assessed for production of interferon-gamma (IFN-gamma) in response to stimulation by HIV-1 antigens. HIV-1 specific responses were compared in a cross-sectional study of two HIV-1-positive patient groups: women not currently on antiretroviral therapy with peripheral CD4 cell counts > 250 x 10(6)/l (n = 12); and women on highly active antiretroviral therapy (HAART) (n = 9)., Methods: Mononuclear cells from peripheral blood or cervicovaginal specimens were assessed in an ELISPOT assay for responses to HIV-1 antigens expressed by recombinant vaccinia viruses. This assay detects primarily CD8 T cells and shows good correlation with MHC class I tetramer staining of cytotoxic T lymphocytes., Results: HIV-1 specific IFN-gamma spot-forming cells were detected in cervicovaginal samples of one out of nine women (11%) on HAART and five out of 12 women (42%) not currently on HAART. In peripheral blood mononuclear cells, HIV-1 specific IFN-gamma spot-forming cells were significantly more numerous in women not currently on HAART than in women on HAART (P = 0.009). In most cases, antigens recognized by mucosal T cells were also recognized by PBMC; however, there were exceptions., Conclusions: HIV-1-specific antigen-reactive T cells may be detected in routine, noninvasive gynecological specimens. The results suggest that cervicovaginal HIV-1-specific T cells may be less numerous in individuals on HAART than in those not on HAART, as shown previously for HIV-1-specific cytotoxic T lymphocytes in the peripheral blood.