Gag p24 Is a Marker of Human Immunodeficiency Virus Expression in Tissues and Correlates With Immune Response.

We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.

Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy.

BACKGROUND: Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy. METHODS: Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry. RESULTS: Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines. CONCLUSIONS: HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.

Circulating CD30+CD4+ T Cells Increase Before Human Immunodeficiency Virus Rebound After Analytical Antiretroviral Treatment Interruption.

BACKGROUND: Identification of nonviral markers of human immunodeficiency virus (HIV) infection that increase before viral rebound during analytical treatment interruption (ATI) may affect HIV persistence research. We previously showed that HIV ribonucleic acid (RNA) is enriched in CD30+CD4+ T cells in many individuals. Here, we studied CD30+CD4+ T-cell dynamics before ATI, during ATI (before detectable plasma RNA), and after HIV rebound. METHODS: Peripheral blood mononuclear cells from 23 participants collected longitudinally from 5 Adult AIDS Clinical Trials Group studies incorporating ATI were included in this study. Flow cytometric characterization of expression of CD30 and markers of T-cell activation and exhaustion were performed along with HIV-1 RNA and deoxyribonucleic acid quantification and measurement of soluble plasma CD30 and CD30 ligand. RESULTS: The percentage of CD4+ T cells expressing CD30 significantly increased from pre-ATI to postinterruption time points before detectible viremia (1.65 mean relative increase, P = .005). Seventy-seven percent of participants experienced an increase in CD30+ cells before viral rebound. In contrast, there were no significant differences between pre-ATI and postinterruption pre-rebound time points in percentages of lymphocytes expressing CD69, CD38/HLA-DR, or PD-1 until after HIV recrudescence. CONCLUSIONS: CD30 may be a surrogate marker of early replication or viral transcriptional activity before detection by routine peripheral blood sampling.

Association of Age-related Macular Degeneration With Mortality in Patients With Acquired Immunodeficiency Syndrome; Role of Systemic Inflammation.

PURPOSE: To evaluate the relationships among age-related macular degeneration (AMD), mortality, and biomarkers of systemic inflammation in patients with acquired immunodeficiency syndrome (AIDS). DESIGN: Case-control study. METHODS: In participants with intermediate-stage AMD at enrollment in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) and 2:1 controls matched for age and sex, cryopreserved baseline plasma specimens were assayed for biomarkers of inflammation, including high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, interferon-γ inducible protein (IP)-10, soluble CD14 (sCD14), soluble CD163 (sCD163), kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP). Main outcome measure was mortality. RESULTS: The study included 189 patients with AMD and 385 controls. In the unadjusted analysis, AMD was associated with mortality (hazard ratio [HR] 1.48; 95% confidence interval [CI] 1.02, 2.15; P = .04). In an adjusted analysis, CRP (HR 1.36; 95% CI 1.08, 1.71; P = .009), IL-6 (HR 1.45; 95% CI 1.11, 1.90; P = .006), and IP-10 (HR 1.41; 95% CI 1.08, 1.84; P = .01) were associated with mortality. In a Cox regression analysis adjusted for human immunodeficiency virus load, blood CD4+ T cell level, CRP, IL-6, and IP-10, the association of AMD with mortality was attenuated (HR 1.08; 95% CI 0.73, 1.59; P = .70), primarily by the addition of the inflammatory biomarkers. CONCLUSIONS: These data suggest that the increased mortality observed in patients with AIDS with AMD is, at least in part, a result of systemic inflammation.

Anti-TNF and thiopurine therapy in pregnant IBD patients does not significantly alter a panel of B-cell and T-cell subsets in 1-year-old infants.

OBJECTIVES: Infants exposed to combination therapy with anti-tumor necrosis factor (anti-TNF) agents and thiopurines may exhibit increased infections at 1 year of age compared to unexposed infants. We hypothesized that this increased risk of infection is due to abnormal development of the newborn immune system. METHODS: We immunophenotyped B-cell and T-cell subsets using multiparameter flow cytometry in 1-year-old infants whose mothers were exposed to therapeutic agents for IBD. We analyzed samples from infants exposed to infliximab (IFX) or adalimumab (ADA) monotherapy (IFX/ADA, n = 11), certolizumab pegol (CZP) monotherapy (CZP, n = 4), IFX or ADA plus thiopurine combination therapy (IFX/ADA + IM, n = 4), and CZP plus thiopurine combination therapy (CZP + IM, n = 2). RESULTS: Percentages of B cells, CD4+ T helper cells, T regulatory cells (Tregs), and CD8+ cytotoxic T cells, were similar among the groups. Infants exposed to combination therapy (IFX/ADA + IM) exhibited trends toward fewer CD27+ B cells, switched memory B cells, plasmablasts, interferon gamma (IFNγ)-producing CD4+ and CD8+ T cells, and CCR5+CD4+ T cells, but these did not reach statistical significance. CONCLUSIONS: Multiparameter immunophenotyping of major B-cell and T-cell subsets suggests that the adaptive newborn immune system develops largely unaltered after exposure to combination therapy as compared to anti-TNF monotherapy.

Chronic stress is associated with reduced circulating hematopoietic progenitor cell number: A maternal caregiving model.

BACKGROUND: Chronic psychological stress is a risk factor for cardiovascular disease and mortality. Circulating hematopoietic progenitor cells (CPCs) maintain vascular homeostasis, correlate with preclinical atherosclerosis, and prospectively predict cardiovascular events. We hypothesize that (1) chronic caregiving stress is related to reduced CPC number, and (2) this may be explained in part by negative interactions within the family. METHODS: We investigated levels of stress and CPCs in 68 healthy mothers - 31 of these had children with an autism spectrum disorder (M-ASD) and 37 had neurotypical children (M-NT). Participants provided fasting blood samples, and CD45+CD34+KDR+ and CD45+CD133+KDR+ CPCs were assayed by flow cytometry. We averaged the blom-transformed scores of both CPCs to create one index. Participants completed the perceived stress scale (PSS), the inventory for depressive symptoms (IDS), and reported on daily interactions with their children and partners, averaged over 7 nights. RESULTS: M-ASD exhibited lower CPCs than M-NT (Cohen's d=0.83; p⩽0.01), controlling for age, BMI, and physical activity. Across the whole sample, positive interactions were related to higher CPCs, and negative interactions to lower CPCs (allp's<0.05). The adverse effects of group on CPCs were significantly mediated through negative interactions with the child (indirect ß=-0.24, p⩽0.01). In the full model, greater age (ß=-0.19, p=0.04), BMI (ß=-0.18, p=0.04), and negative interactions with the child (ß=-0.33, p<0.01) were independently associated with lower CPCs. M-ASD had a less healthy lipid profile (total cholesterol/HDL), which in turn, was associated with lower CPCs. CONCLUSIONS: Chronic stress adversely impacts CPC number, an early-stage biomarker that predicts subclinical atherosclerosis and future CVD events, independent of traditional cardiovascular risk factors and inflammatory factors. Among maternal caregivers, child-related interpersonal stress appears to be a key psychological predictor of stress-related CVD risk.

Persistent HIV Type 1 Seronegative Status Is Associated With Lower CD8+ T-Cell Activation.

We leveraged data from the Preexposure Prophylaxis Initiative (iPrEx), a global trial of preexposure chemoprophylaxis against human immunodeficiency virus type 1 (HIV-1) infection, to compare T-cell activation between those who remained negative for HIV-1 and those who became infected during the trial. The frequency of CD38(+)HLA-DR(+) CD8(+) T cells was greater in those who seroconverted, relative to the frequency in those who remained uninfected (1.30% vs 0.82%, respectively; P = .005). This translated to an odds ratio of 4.26 (95% confidence interval, 1.54-11.78) for the association between CD8(+) T-cell activation and infection with HIV-1. T-cell activation may be a biomarker for elevated HIV-1 infection risk.

Ex vivo Human Natural Killer (NK) Cell Stimulation and Intracellular IFNγ and CD107a Cytokine Staining.

Natural killer (NK) cells comprise 5-20% of peripheral blood mononuclear cells (PBMC) in humans. In addition to their fundamental roles in the defense against viral infections and tumor surveillance, NK cells help shape adaptive immune responses through their production of cytokines. NK cells are traditionally identified as CD3neg, CD14neg, CD19neg lymphocytes expressing CD56. Using a combination of markers that includes CD56 and CD7 greatly increases the ability to define the phenotype and function of NK cell subsets. Two key markers of NK cell function are the production of IFNγ and the release of cytotoxic granules measured by the expression of CD107a. Here we describe a method to assess IFNγ and CD107a expression in NK cells following stimulation with target cells or cytokines. This method can be used to assess the general functional capacity of NK cells in peripheral blood mononuclear cells from a wide range of study participants.

The CD8⁺ memory stem T cell (T(SCM)) subset is associated with improved prognosis in chronic HIV-1 infection.

UNLABELLED: Memory stem T cells (T(SCM)) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. The hallmarks of HIV-1 pathogenesis are CD4(+) T cell depletion and abnormal cellular activation. We investigated the impact of HIV-1 infection on the T(SCM) compartment, as well as any protective role these cells may have in disease progression, by characterizing this subset in a cohort of 113 subjects with various degrees of viral control on and off highly active antiretroviral therapy (HAART). We observed that the frequency of CD8(+) T(SCM) was decreased in all individuals with chronic, untreated HIV-1 infection and that HAART had a restorative effect on this subset. In contrast, natural controllers of HIV-1 had the highest absolute number of CD4(+) T(SCM) cells among all of the infected groups. The frequency of CD4(+) T(SCM) predicted higher CD8(+) T(SCM) frequencies, consistent with a role for the CD4(+) subset in helping to maintain CD8(+) memory T cells. In addition, T(SCM) appeared to be progenitors for effector T cells (TEM), as these two compartments were inversely correlated. Increased frequencies of CD8(+) T(SCM) predicted lower viral loads, higher CD4(+) counts, and less CD8(+) T cell activation. Finally, we found that T(SCM) express the mucosal homing integrin α4ß7 and can be identified in gut-associated lymphoid tissue (GALT). The frequency of mucosal CD4(+) T(SCM) was inversely correlated with that in the blood, potentially reflecting the ability of these self-renewing cells to migrate to a crucial site of ongoing viral replication and CD4(+) T cell depletion. IMPORTANCE: HIV-1 infection leads to profound impairment of the immune system. T(SCM) constitute a recently identified lymphocyte subset with stem cell-like qualities, including the ability to generate other memory T cell subtypes, and are therefore likely to play an important role in controlling viral infection. We investigated the relationship between the size of the CD8(+) T(SCM) compartment and HIV-1 disease progression in a cohort of chronically infected individuals. Our results suggest that HAART restores a normal frequency of CD8(+) T(SCM) and that the natural preservation of this subset in the setting of untreated HIV-1 infection is associated with improved viral control and immunity. Therefore, the CD8(+) T(SCM) population may represent a correlate of protection in chronic HIV-1 infection that is directly relevant to the design of T cell-based vaccines, adoptive immunotherapy approaches, or the pharmacologic induction of T(SCM).

Invariant natural killer T (iNKT) cell exhaustion in sarcoidosis.

Invariant natural killer T (iNKT) cells are integral components of immune responses during many chronic diseases, yet their surface phenotypes, subset distribution, and polyfunctional capacity in this environment are largely unknown. Therefore, using flow cytometry, we determined iNKT cell phenotypic and functional characteristics in subjects with chronic inflammatory disease sarcoidosis and matched controls. We found that sarcoidosis subjects displayed lower iNKT-cell frequencies, which correlated with lung fibrosis, C-reactive protein levels, and other measures of clinical disease. The CD4(-) CD8(-) (double negative, DN) iNKT-cell population was selectively lower in diseased individuals and the remaining DN iNKT cells exhibited higher frequencies of the activation markers CD69 and CD56. Functionally, both total IFN-γ(+) and the dual-functional IFN-γ(+) TNF-α(+) iNKT cells were decreased in sarcoidosis subjects and these functional defects correlated with total iNKT-cell circulating frequencies. As the loss of polyfunctionality can reflect functional exhaustion, we measured the surface antigens programmed death-1 receptor and CD57 and found that levels inversely correlated with dual-functional iNKT-cell percentages. These findings reveal that, similar to traditional T cells, iNKT cells may also undergo functional exhaustion, and that circulating iNKT-cell frequencies reflect these defects. Programmed death-1 receptor antagonists may therefore be attractive therapeutic candidates for sarcoidosis and other iNKT-cell-mediated chronic diseases.

Targeting of conserved gag-epitopes in early HIV infection is associated with lower plasma viral load and slower CD4(+) T cell depletion.

We aimed to investigate whether the character of the immunodominant HIV-Gag peptide (variable or conserved) targeted by CD8(+) T cells in early HIV infection would influence the quality and quantity of T cell responses, and whether this would affect the rate of disease progression. Treatment-naive HIV-infected study subjects within the OPTIONS cohort at the University of California, San Francisco, were monitored from an estimated 44 days postinfection for up to 6 years. CD8(+) T cells responses targeting HLA-matched HIV-Gag-epitopes were identified and characterized by multicolor flow cytometry. The autologous HIV gag sequences were obtained. We demonstrate that patients targeting a conserved HIV-Gag-epitope in early infection maintained their epitope-specific CD8(+) T cell response throughout the study period. Patients targeting a variable epitope showed decreased immune responses over time, although there was no limitation of the functional profile, and they were likely to target additional variable epitopes. Maintained immune responses to conserved epitopes were associated with no or limited sequence evolution within the targeted epitope. Patients with immune responses targeting conserved epitopes had a significantly lower median viral load over time compared to patients with responses targeting a variable epitope (0.63 log(10) difference). Furthermore, the rate of CD4(+) T cell decline was slower for subjects targeting a conserved epitope (0.85% per month) compared to subjects targeting a variable epitope (1.85% per month). Previous studies have shown that targeting of antigens based on specific HLA types is associated with a better disease course. In this study we show that categorizing epitopes based on their variability is associated with clinical outcome.

The calm mouse: an animal model of stress reduction.

Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a "calm mouse model" with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.

CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset.

Natural killer (NK) cells are innate immune lymphocytes that express a heterogeneous repertoire of germline-encoded receptors and undergo a distinct pattern of maturation. CD57 is a marker of terminal differentiation on human CD8(+) T cells. Very few newborn or fetal NK cells express CD57; however, the frequency of CD57-bearing NK cells increases with age. We assessed the transcriptional, phenotypic, and functional differences between CD57(+) and CD57(-) NK cells within the CD56(dim) mature NK subset. CD57(+) NK cells express a repertoire of NK-cell receptors, suggestive of a more mature phenotype, and proliferate less when stimulated with target cells and/or cytokines. By contrast, a higher frequency of CD57(+) NK cells produced interferon-γ and demonstrated more potent lytic activity when these cells were stimulated through the activating receptor CD16; however, they are less responsive to stimulation by interleukin-12 and interleukin-18. Finally, CD57 expression is induced on CD57(-)CD56(dim) NK cells after activation by interleukin-2. A combination of a mature phenotype, a higher cytotoxic capacity, a higher sensitivity to stimulation via CD16, with a decreased responsiveness to cytokines, and a decreased capacity to proliferate suggest that CD57(+) NK cells are highly mature and might be terminally differentiated.

Functionally distinct subsets of human NK cells and monocyte/DC-like cells identified by coexpression of CD56, CD7, and CD4.

The lack of natural killer (NK) cell-specific markers, as well as the overlap among several common surface antigens and functional properties, has obscured the delineation between NK cells and dendritic cells. Here, novel subsets of peripheral blood CD3/14/19(neg) NK cells and monocyte/dendritic cell (DC)-like cells were identified on the basis of CD7 and CD4 expression. Coexpression of CD7 and CD56 differentiates NK cells from CD56+ monocyte/DC-like cells, which lack CD7. In contrast to CD7+CD56+ NK cells, CD7(neg)CD56+ cells lack expression of NK cell-associated markers, but share commonalities in their expression of various monocyte/DC-associated markers. Using CD7, we observed approximately 60% of CD4+CD56+ cells were CD7(neg) cells, indicating the actual frequency of activated CD4+ NK cells is much lower in the blood than previously recognized. Functionally, only CD7+ NK cells secrete gamma interferon (IFNgamma) and degranulate after interleukin-12 (IL-12) plus IL-18 or K562 target cell stimulation. Furthermore, using CD7 to separate CD56+ NK cells and CD56+ myeloid cells, we demonstrate that unlike resting CD7+CD56+ NK cells, the CD7(neg)CD56+ myeloid cells stimulate a potent allogeneic response. Our data indicate that CD7 and CD56 coexpression discriminates NK cells from CD7(neg)CD56+ monocyte/DC-like cells, thereby improving our ability to study the intricacies of NK-cell subset phenotypes and functions in vivo.

Gamma/Delta T cell mRNA levels decrease at mucosal sites and increase at lymphoid sites following an oral SIV infection of macaques.

The oral and esophageal mucosa have been identified as possible sites of HIV/SIV entry following oral infection. Here, gamma/delta (gammadelta) T cells, a multi-functional T cell subset, were assessed at oral/esophageal mucosa and lymphoid sites at the earliest times (1-14 days) post-oral SIV inoculation utilizing quantitative RT-PCR. During these earliest times post-infection, decreased gammadelta TCR mRNA levels were observed at the oral gingiva and esophageal mucosa, while increased levels were observed within regional lymph nodes (cervical and retropharyngeal). Higher lymph node gammadelta TCR levels were associated with increased mRNA expression of the lymphoid homing chemokine/receptor (CCL21/CCR7) pair in these lymph nodes. In contrast to gammadelta TCR levels, CD4 mRNA expression remained relatively stable through 4 days post-infection, and depletion of CD4 T cells was only evident after 7 or 14 days post-infection. The decrease of gammadelta T cell mRNA from mucosal sites and the corresponding increase at lymphoid sites suggest a rapid redistribution of these immune cells at these earliest times post-SIV infection.

Gamma/Delta T-cell functional responses differ after pathogenic human immunodeficiency virus and nonpathogenic simian immunodeficiency virus infections.

The objective of this study was to functionally assess gamma/delta (gammadelta) T cells following pathogenic human immunodeficiency virus (HIV) infection of humans and nonpathogenic simian immunodeficiency virus (SIV) infection of sooty mangabeys. gammadelta T cells were obtained from peripheral blood samples from patients and sooty mangabeys that exhibited either a CD4-healthy (>200 CD4(+) T cells/mul blood) or CD4-low (<200 CD4 cells/mul blood) phenotype. Cytokine flow cytometry was utilized to assess production of Th1 cytokines tumor necrosis factor alpha and gamma interferon following ex vivo stimulation with either phorbol myristate acetate/ionomycin or the Vdelta2 gammadelta T-cell receptor agonist isopentenyl pyrophosphate. Sooty mangabeys were observed to have higher percentages of gammadelta T cells in their peripheral blood than humans did. Following stimulation, gammadelta T cells from SIV-positive (SIV(+)) mangabeys maintained or increased their ability to express the Th1 cytokines regardless of CD4(+) T-cell levels. In contrast, HIV-positive (HIV(+)) patients exhibited a decreased percentage of gammadelta T cells expressing Th1 cytokines following stimulation. This dysfunction is primarily within the Vdelta2(+) gammadelta T-cell subset which incurred both a decreased overall level in the blood and a reduced Th1 cytokine production. Patients treated with highly active antiretroviral therapy exhibited a partial restoration in their gammadelta T-cell Th1 cytokine response that was intermediate between the responses of the uninfected and HIV(+) patients. The SIV(+) sooty mangabey natural hosts, which do not proceed to clinical AIDS, provide evidence that gammadelta T-cell dysfunction occurs in HIV(+) patients and may contribute to HIV disease progression.

Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys.

Simian immunodeficiency virus (SIV) SIV(smm) naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIV(mac) of humans and macaques, respectively. In previous studies we characterized SIV(smm) diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the colony of SMs housed at the Yerkes National Primate Research Center, at least four SIV(smm) subtypes cocirculate, with the vast majority of animals infected with SIV(smm) subtype 1, 2, or 3, resulting in the emergence of occasional recombinant forms. While SIV(smm)-infected SMs show a typically nonpathogenic course of infection, we have observed that different SIV(smm) subtypes are in fact associated with specific immunologic features. Notably, while subtypes 1, 2, and 3 are associated with a very benign course of infection and preservation of normal CD4+ T-cell counts, three out of four SMs infected with subtype 5 show a significant depletion of CD4+ T cells. The fact that virus replication in SMs infected with subtype 5 is similar to that in SMs infected with other SIV(smm) subtypes suggests that the subtype 5-associated CD4+ T-cell depletion is unlikely to simply reflect higher levels of virus-mediated direct killing of CD4+ T-cells. Taken together, this systematic analysis of the subtype-specific features of SIV(smm) infection in natural SM hosts identifies subtype-specific differences in the pathogenicity of SIV(smm) infection.

Mucosal innate immune response associated with a timely humoral immune response and slower disease progression after oral transmission of simian immunodeficiency virus to rhesus macaques.

Mucosal transmission is the predominant mode of human immunodeficiency virus (HIV) infection worldwide, and the mucosal innate interferon response represents an important component of the earliest host response to the infection. Our goal here was to assess the changes in mRNA expression of innate mucosal genes after oral simian immunodeficiency virus (SIV) inoculation of rhesus macaques (Macaca mulatta) that were followed throughout their course of disease progression. The SIV plasma viral load was highest in the macaque that progressed rapidly to simian AIDS (99 days) and lowest in the macaque that progressed more slowly (>700 days). The mRNA levels of six innate/effector genes in the oral mucosa indicated that slower disease progression was associated with increased expression of these genes. This distinction was most evident when comparing the slowest-progressing macaque to the intermediate and rapid progressors. Expression levels of alpha and gamma interferons, the antiviral interferon-stimulated gene product 2'-5' oligoadenylate synthetase (OAS), and the chemokines CXCL9 and CXCL10 in the slow progressor were elevated at each of the three oral mucosal biopsy time points examined (day 2 to 4, 14 to 21, and day 70 postinfection). In contrast, the more rapidly progressing macaques demonstrated elevated levels of these cytokine/chemokine mRNA at lymph nodes, coincident with decreased levels at the mucosal sites, and a decreased ability to elicit an effective anti-SIV antibody response. These data provide evidence that a robust mucosal innate/effector immune response is beneficial following lentiviral exposure; however, it is likely that the anatomical location and timing of the response need to be coordinated to permit an effective immune response able to delay progression to simian AIDS.