HIV-infected Long-term Nonprogressors Research Articles

The Role of Innate Immunity in Natural Elite Controllers of HIV-1 Infection.

The natural process of human immunodeficiency virus type 1(HIV-1) infection is characterized by high viral load, immune cell exhaustion, and immunodeficiency, which eventually leads to the stage of acquired immunodeficiency syndrome (AIDS) and opportunistic infections. Rapidly progressing HIV-1 individuals often die of AIDS several years after infection without treatment. The promotion of ART greatly prolongs the survival time of HIV-infected persons. However, some patients have incomplete immune function reconstruction after ART due to latent storage of HIV-infected cells. Therefore, how to achieve a functional cure has always been the focus and hot spot of global AIDS research. Fortunately, the emergence of ECs/LTNPs who can control virus replication naturally has ignited new hope for realizing a functional cure for AIDS. Recently, a special category of infected individuals has attracted attention that can delay the progression of the disease more rigorously than the natural progression of HIV-1 infection described above. These patients are characterized by years of HIV-1 infection, long-term asymptomatic status, and normal CD4+T cell count without ART, classified as HIV-infected long-term nonprogressors (LTNPs) and elite controllers (ECs). Numerous studies have shown that the host and virus jointly determine the progression of HIV-1 infection, in which the level of innate immunity activation plays an important role. As the first line of defense against pathogen invasion, innate immunity is also a bridge to induce adaptive immunity. Compared with natural progressors, innate immunity plays an antiviral role in HIV-1 infection by inducing or activating many innate immune-related factors in the natural ECs. Learning the regulation of ECs immunity, especially the innate immunity in different characteristics, and thus studying the mechanism of the control of disease progression naturally, will contribute to the realization of the functional cure of AIDS. Therefore, this review will explore the relationship between innate immunity and disease progression in ECs of HIV-1 infection from the aspects of innate immune cells, signaling pathways, cytokines, which is helpful to provide new targets and theoretical references for the functional cure, prevention and control of AIDS, and development of a vaccine.

Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection

Circulating memory B cells are severely reduced in the peripheral blood of HIV-1-infected patients. We investigated whether dysfunctional serologic memory to non-HIV antigens is related to disease progression by evaluating the frequency of memory B cells, plasma IgG, plasma levels of antibodies to measles, and Streptococcus pneumoniae, and enumerating measles-specific antibody-secreting cells in patients with primary, chronic, and long-term nonprogressive HIV-1 infection. We also evaluated the in vitro production of IgM and IgG antibodies against measles and S pneumoniae antigens following polyclonal activation of peripheral blood mononuclear cells (PBMCs) from patients. The percentage of memory B cells correlated with CD4+ T-cell counts in patients, thus representing a marker of disease progression. While patients with primary and chronic infection had severe defects in serologic memory, long-term nonprogressors had memory B-cell frequency and levels of antigen-specific antibodies comparable with controls. We also evaluated the effect of antiretroviral therapy on these serologic memory defects and found that antiretroviral therapy did not restore serologic memory in primary or in chronic infection. We suggest that HIV infection impairs maintenance of long-term serologic immunity to HIV-1-unrelated antigens and this defect is initiated early in infection. This may have important consequences for the response of HIV-infected patients to immunizations.

Enriched LPS Staining within the Germinal Center of a Lymph Node from an HIV-Infected Long-Term Nonprogressor but Not from Progressors.

An increased level of microbial translocation has been observed in HIV-infected individuals. The host response to microbial translocation is compromised in HIV-infected progressors but remains unknown in HIV-infected long-term nonprogressors (LTNPs). To evaluate microbial translocation in HIV, we assessed lipopolysaccharide (LPS) immunohistochemistry staining in lymph nodes. We found enriched bacterial LPS immunohistochemistry staining in the germinal center of a lymph node from an HIV-infected LTNP, evenly distributed from three progressors with impaired germinal center structures and rarely detected from two HIV-negative individuals. The impaired germinal center structures were consistent with collagen deposition in lymph nodes using immunohistochemistry staining. These results suggest greater immune responses against bacterial LPS translocation in LTNPs, which may reveal an important mechanism in controlling microbial translocation and disease progression in HIV LTNPs.

Monocyte Based Correlates of Immune Activation and Viremia in HIV-Infected Long-Term Non-Progressors.

Background: Disease progression monitoring through CD4 counts alone can be inadequate in HIV infection as ongoing immune activation may result in Serious non-AIDS events (SNAEs). SNAEs involve monocyte activation driven chronic inflammation with significant sequelae observed even during HAART. Here, we attempted to delineate functional monocyte based signatures across stages of HIV disease progression.Methods: Participants spanning four cohorts were recruited—pre-ART (PA; <7 years of infection; n = 20), long-term non-progressors (LTNP; >7 years of infection, CD4 > 350 cells/μL, n = 20), individuals on therapy (ART; n = 18) and seronegative controls (SN; n = 15). Immunophenotyping of monocyte subsets and evaluation of expression of HIV-binding receptors—CD4 and CCR5, marker of immune activation- HLA-DR and M2 phenotype—mannose receptor (CD206) was followed by association of monocyte-specific parameters with conventional markers of disease progression such as absolute CD4 count, CD4/CD8 ratio, viral load, and T cell activation.Results: A significant expansion of intermediate monocytes (CD14++CD16+) with a concomitant decline in classical subset (CD14++CD16–) was observed in all infected cohorts compared to seronegative controls. In addition, an expansion of the non-classical subset (CD14+CD16++) was observed in long-term non-progressors. Dysregulation in monocyte subsets associated with CD4 count and CD4/CD8 ratio in PAs but not in LTNPs. We report for the first time that expression of CD206 is most prominent on intermediate monocytes which also have the highest expression of CD4, CCR5, and HLA-DR. Despite preserved CD4 counts, LTNPs had similar immune activation profiles to PAs, as evidenced by elevated HLA-DR expression across monocyte subsets. HLA-DR expression, similar to that in SNs, observed in the ART group indicated partial immune restoration within the monocyte compartment. Increased CD206 expression on monocytes together with frequency of activated CD4+ T lymphocytes (HLA-DR+CD38+) showed significant and positive association with viral load in LTNPs, but not PAs.Conclusion: Our results describe for the first time the presence of monocyte dysregulation involving increased activation in LTNPs, who, in spite of preserved CD4 counts, may remain susceptible to prolonged effects of systemic inflammation and highlight CD206, as a unique non-T correlate of viremia, in viremic non-progression.

An integrative genomic analysis of transcriptional profiles identifies characteristic genes and patterns in HIV-infected long-term non-progressors and elite controllers

BackgroundDespite that most HIV-infected individuals experience progressive CD4+ T cell loss and develop AIDS, a minority of HIV-infected individuals remain asymptomatic and maintain high level CD4+ T cell counts several years after seroconversion. Efforts have been made to understand the determinants of the nonprogressive status, exemplified by the clinical course of elite controllers (ECs) who maintain an undetectable viremia and viremic nonprogressors (VNPs) who have a normal CD4+ count in spite of circulating viral load. However, the intrinsic mechanism underlying nonprogression remained elusive. In this study, we performed an integrative analysis of transcriptional profiles to pinpoint the underlying mechanism for a naturally occurring viral control.MethodsThree microarray datasets, reporting mRNA expression of the LTNPs or ECs in HIV-infected patients, were retrieved from Gene Expression Ominbus (GEO) or Arrayexpress databases. These datasets, profiled on the same type of microarray chip, were selected and merged by a bioinformatic approach to build a meta-analysis derived transcriptome (MADNT). In addition, we investigated the different transcriptional pathways and potential biomarkers in CD4+ and CD8+ cells in ECs and whole blood in VNPs compared to HIV progressors. The combined transcriptome and each subgroup was subject to gene set enrichment analysis and weighted co-expression network analysis to search potential transcription patterns related to the non-progressive status.Results30 up-regulated genes and 83 down-regulated genes were identified in lymphocytes from integrative meta-analysis of expression data. The interferon response and innate immune activation was reduced in both CD4+ and CD8+ T cells from ECs. Several characteristic genes including CMPK1, CBX7, EIF3L, EIF4A and ZNF395 were indicated to be highly correlated with viremic control. Besides that, we indicated that the reduction of ribosome components and blockade of translation facilitated AIDS disease progression. Most interestingly, among VNPs who have a relatively high viral load, we detected a two gene-interaction networks which showed a strong correlation to immune control even with a rigorous statistical threshold (p value = 2−e4 and p value = 0.004, respectively) by WGCNA.ConclusionsWe have identified differentially expressed genes and transcriptional patterns in ECs and VNPs compared to normal chronic HIV-infected individuals. Our study provides new insights into the pathogenesis of HIV and AIDS and clues for the therapeutic strategies for anti-retroviral administration.

HIV-specific CD4+Th17 cells from HIV infected long-term non-progressors exhibit lower CTLA-4 expression and reduced apoptosis

Progressive HIV infection is marked with reduced frequency and impaired function of Th17 cells. Since T-cell functional responses are regulated by various inhibitory receptors; we examined the expression profile of CTLA-4, PD-1, Tim-3 and apoptotic marker: Caspase-3 on virus-specific Th17 cells from HIV-infected Long-Term Non-Progressors (LTNPs), chronic disease progressors and HIV-uninfected healthy controls (HC) using flowcytometry. Real-time PCR was done to analyze the mRNA expression of Th17 and Treg specific genes. LTNPs showed higher frequencies of HIV-specific Th17 cells; higher mRNA expression of IL-17, IL-22 while lower expression of IL-10; along with lower Caspase-3 expression than the progressors. Among inhibitory receptors, expression of CTLA-4 was 27 and 8 fold; PD-1 was 8 and 6 fold while Tim-3 was 7 and 6 fold higher in progressors and LTNPs respectively than HC. Among HIV-infected patients, LTNPs had 3-fold lower expression of CTLA-4 on HIV-specific Th17 cells than progressors (p = 0.06). Caspase-3+ve Th17 cells were associated with HIV-specific Th17 cells expressing CTLA-4 (r = 0.66;p < 0.0001), PD-1 (r = 0.40;p = 0.02) and Tim-3 (r = 0.35;p = 0.04). To conclude, virus-specific Th17 cells from LTNP maintained IL-17 production, expressed low levels of CTLA-4 and reduced apoptosis. The study suggests that such functional competence of Th17 cells could be one of the factors in maintenance of non-progressive HIV infection.

HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India.

Background: Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective: This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods: HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results: Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion: LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

A potentially protective role of IL-18 Binding Protein in HIV-infected Long-Term Non-Progressors

An imbalance between IL-18 and its antagonist, IL-18 Binding Protein, occurs in the circulation of HIV-infected individuals. We show here for the first time that HIV-infected Long Term Non-Progressors (LTNPs) do not develop this imbalance, and maintain normal levels of IL-18BP in the circulation. Their circulating levels of the antagonist correlate negatively with viral loads and show a positive trend with CD4+ T cells counts. The maintenance of normal production of IL-18BP may contribute, at least in part, to the ability of LTNPs to delay AIDS progression.

The Effects of RANTES Polymorphisms on Susceptibility to HIV-1 Infection and Disease Progression: Evidence from an Updated Meta-Analysis.

Associations of regulated on activation, normal T cell expressed and secreted (RANTES) -403G/A, -28C/G, and In1.1T/C polymorphisms with HIV-1 infection and the progression of HIV-1 disease have been widely reported with inconsistent results. To clarify this situation, we performed an updated meta-analysis of all available studies from PubMed, EMBASE, and the China National Knowledge Infrastructure. A total of 24 eligible studies involving more than 10,000 subjects were included. By using the healthy controls, we found that -403G/A polymorphism was significantly associated with reduced susceptibility to HIV-1 infection in G/A+A/A versus GG (odds ratio [OR] = 0.755, 95% confidence interval [CI] = 0.581-0.982); and a significantly decreased risk was also found for -28C/G polymorphisms (G vs. C, OR = 0.804, 95% CI = 0.696-0.927; G/G+C/G vs. C/C, OR = 0.826, 95% CI = 0.704-0.969). Whereas for In1.1T/C polymorphism, increased risk of HIV-1 infection was revealed (C vs. T, OR = 1.216, 95% CI = 1.047-1.430; T/C vs. T/T, OR = 1.68, 95% CI = 1.263-2.234; T/C+T/T vs. C/C, OR = 1.466, 95% CI = 1.147-1.875). Subgroup analyses by ethnicity showed significant association among Asians, but not among Caucasians. When HIV-1-exposed seronegative (HESN) controls were used, no significant association was detected. Moreover, -403G/A and -28C/G polymorphisms were also not associated with long-term nonprogressive HIV-1 infection (all p > .05). This meta-analysis suggests that RANTES -403G/A and -28C/G polymorphisms confer possible protection against HIV-1 infection, whereas In1.1T/C polymorphism may increase risk of HIV-1 infection, especially in Asians. These results may contribute to finding a theoretical basis for effective control strategies against HIV/AIDS. Further investigations are needed to validate our conclusions.

Mitochondrial and apoptotic in vitro modelling of differential HIV-1 progression and antiretroviral toxicity.

Ex vivo analysis of mitochondrial function may reveal HIV progression and the impact of ART. We propose a mitochondrial and apoptotic in vitro model using Jurkat T cells incubated with plasma. The objectives of this study were to evaluate mitochondrial and apoptotic lesions in this model in relation to HIV progression, and to assess the effect of >1 year of standard non-thymidine-containing therapy. This was a cross-sectional comparison among three age- and gender-matched groups (n = 19 × 3): healthy non-HIV-infected participants, HIV-infected long-term non-progressors (LTNPs) and standard antiretroviral-naive chronically infected patients [standard progressors (Sps)], longitudinally evaluated before (Sp1) and after (Sp2) >1 year of efavirenz + tenofovir + emtricitabine therapy. We analysed mitochondrial DNA content by RT-PCR, mitochondrial function by spectrophotometry, mitochondrial protein synthesis by western blot analysis, mitochondrial dynamics by western blot analysis (MFN2), apoptotic transition pore formation by western blot analysis (VDAC-1) and mitochondrial membrane potential and annexin V/propidium iodide fluorescence by flow cytometry. There was a decreasing non-significant trend towards lower mitochondrial parameters for HIV-infected values with respect to uninfected control reference values. HIV progression (LTNP versus Sp1) was associated with decreased mitochondrial genetic, functional and translational parameters, which partially recovered after treatment intervention (Sp2). Mitochondrial fusion showed a trend to decrease non-significantly in Sp patients compared with LTNP patients, especially after therapy. All apoptotic parameters showed a trend to increase in Sp1 with respect to LTNP, followed by recovery in Sp2. We proposed an in vitro model for mitochondrial and apoptotic assessment to test the effects of HIV infection and its therapy, resembling in vivo conditions. This model could be useful for clinical research purposes.

The number of CCR5 expressing CD4+ T lymphocytes is lower in HIV-infected long-term non-progressors with viral control compared to normal progressors: a cross-sectional study

BackgroundThe HIV co-receptors CXCR4 and CCR5 play an important role in HIV infection and replication. Therefore we hypothesize that long-term non-progressors (LTNP) with viral control have lower expression of CCR5 and CXCR4 on CD4+ cells, specifically on memory T-lymphocytes since they are the primary target cells of HIV.MethodsIn this cross-sectional study, we included five HIV-infected LTNP with viral control (CD4 > 750 cell/μl & HIV < 50 copies for ≥2 years), thirteen HIV-infected and seven HIV-uninfected individuals at Radboud UMC Nijmegen, the Netherlands. We determined the CCR5 and CXCR4 expression among CD4+ and CD8+ lymphocyte subsets; memory (CD45RO+), naïve (CD45RA+) cells and regulatory T-cells (CD4+CD25highFoxP3+). In addition, CCR5∆32 polymorphism is related with disease progression and was therefore determined using polymerase chain reaction.ResultsThe percentage of CCR5-expressing CD4+ cells of LTNP was comparable with healthy controls; whereas HIV-infected individuals showed more CCR5-expressing cells. This was observed in memory and naïve CD4+ cells, but not in regulatory T-cells. The mean fluorescence intensity of CCR5-expressing CD4+ cells was similar in all groups. All groups had comparable percentages of CXCR4-expressing cells. The mean fluorescence intensity of CXCR4-expressing cells was significantly higher in HIV-infected normally progressors in both memory and naïve CD4+ cells, but not in CD8+ cells. The CCR5∆32 polymorphism was not related to group.ConclusionsWe show that HIV affects -directly or indirectly- the expression of CCR5 in CD4+ T-lymphocytes; yet this effect is not seen in LTNP with viral control. Avoiding upregulation of CCR5 could be an important method via which LTNP counteracts the effects of HIV and suppresses viral replication. Exploring how LTNP suppress the upregulation of CCR5 could be an important step for discovering new therapeutics.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0683-0) contains supplementary material, which is available to authorized users.

HIV-1 and HIV-2 differentially mature plasmacytoid dendritic cells into IFN-producing cells or APCs.

HIV-1 causes a progressive impairment of immune function. HIV-2 is a naturally attenuated form of HIV, and HIV-2 patients display a slow-progressing disease. The leading hypothesis for the difference in disease phenotype between HIV-1 and HIV-2 is that more efficient T cell-mediated immunity allows for immune-mediated control of HIV-2 infection, similar to that observed in the minority of HIV-1-infected long-term nonprogressors. Understanding how HIV-1 and HIV-2 differentially influence the immune function may highlight critical mechanisms determining disease outcome. We investigated the effects of exposing primary human peripheral blood cells to HIV-1 or HIV-2 in vitro. HIV-2 induced a gene expression profile distinct from HIV-1, characterized by reduced type I IFN, despite similar upregulation of IFN-stimulated genes and viral restriction factors. HIV-2 favored plasmacytoid dendritic cell (pDC) differentiation into cells with an APC phenotype rather than IFN-α-producing cells. HIV-2, but not HIV-1, inhibited IFN-α production in response to CpG-A. The balance between pDC maturation into IFN-α-producing cells or development of an APC phenotype differentiates the early response against HIV-1 and HIV-2. We propose that divergent paths of pDC differentiation driven by HIV-1 and HIV-2 cause the observed differences in pathogenicity between the two viruses.

Loss of Viral Control in a Subset of HIV-Infected Long-term Non-progressors Is Associated with a Decline of an Array of Antiviral Responses

Loss of Viral Control in a Subset of HIV-Infected Long-term Non-progressors Is Associated with a Decline of an Array of Antiviral Responses

Psychosocial Profile and Lived Experience of HIV-infected Long-term Nonprogressors: A Mixed Method Study

The goal of this mixed method study was to describe the psychosocial profile of HIV-infected persons identified as long-term nonprogressors (LTNP), and their experiences of nonprogression. Data were collected from 24 participants with a mean age of 48 years and a mean duration of infection of 14 years. Results show rather moderate levels of anxiety and depression symptoms and a modest mean score of social support. Participants adapted by using acceptance, positive restructuring, and active coping strategies. Seven themes marked the experience: (a) reacting to announcement and dealing with diagnosis, (b) valuing interpersonal relations and well-being, (c) making changes in life, (d) coping with stress, (e) dealing with health care, (f) beliefs about reasons for nonprogression, and (g) living positively while dreading progression. The findings enrich a field of knowledge that has had little attention so far and shed light on the psychosocial profile of LTNP and their experiences of nonprogression.

Viremic long-term nonprogressive HIV-1 infection is not associated with abnormalities in known Nef functions

BackgroundA small minority of HIV-1-infected individuals show low levels of immune activation and do not develop immunodeficiency despite high viral loads. Since the accessory viral Nef protein modulates T cell activation and plays a key role in the pathogenesis of AIDS, we investigated whether specific properties of Nef may be associated with this highly unusual clinical outcome of HIV-1 infection.FindingsComprehensive functional analyses of sequential HIV-1 strains from three viremic long-term non-progressors (VNP) showed that they encode full-length Nef proteins that are capable of modulating CD4, CD28, CD8ß, MHC-I and CD74 cell surface expression. Similar to Nef proteins from HIV-1-infected individuals with progressive infection (P-Nefs) and unlike Nefs from simian immunodeficiency viruses (SIVs) that do not cause chronic immune activation and disease in their natural simian hosts, VNP-Nefs were generally unable to down-modulate TCR-CD3 cell surface expression to block T cell activation and apoptosis. On average, VNP-Nefs suppressed NF-AT activation less effectively than P-Nefs and were slightly less active in enhancing NF-κB activity. Finally, we found that VNP-Nefs increased virion infectivity and enhanced HIV-1 replication and cytopathicity in primary human cells and in ex vivo infected lymphoid tissues.ConclusionsOur results show that nef alleles from VNPs and progressors of HIV-1 infection show only modest differences in established functions. Thus, the lack of chronic immune activation and disease progression in HIV-1-infected VNPs is apparently not associated with unusual functional properties of the accessory viral Nef protein.

Immunoregulatory T Cells May Be Involved in Preserving CD4 T Cell Counts in HIV-Infected Long-Term Nonprogressors and Controllers

HIV-infected controllers control viral replication and maintain normal CD4 T cell counts. Long-term nonprogressors (LTNPs) also maintain normal CD4 T cell counts but have ongoing viral replication. We hypothesized that immunoregulatory mechanisms are involved in preserved CD4 T cell counts in controllers and in LTNPs. Twenty HIV-infected viremic controllers, 5 elite controllers (ECs), and 14 LTNPs were included in this cross-sectional study. For comparison, 25 progressors and 34 healthy controls were included. Regulatory T cells (Tregs), Treg subpopulations, CD161+Th17 cells, and CD3+CD8+CD161(high)Tc17 cells in peripheral blood were measured using flow cytometry. Tregs in lymphoid tissue were determined in tonsil biopsies and evaluated using immunolabeling. The production of transforming growth factor beta (TGF-β), interleukin (IL)-10, and IL-17 upon stimulation with phytohemagglutinin in peripheral blood was determined by Luminex. All groups of HIV-infected patients displayed similar percentages of Tregs in both peripheral blood and lymphoid tissue. However, a larger percentage of Tregs in ECs and LTNPs were activated compared with that in controls, progressors, and viremic controllers. Further, ECs as the only group of HIV-infected patients, displayed elevated percentages of CD161+Th17 cells, preserved CD3+CD8+CD161(high)Tc17 cells, and preserved IL-10 production. Overall, Treg percentage was similar in both blood and lymphoid tissue in all groups of patients and controls. However, both ECs and LTNPs displayed a large proportion of activated Tregs suggesting immunoregulatory mechanisms to be involved in preserving CD4 T cell counts in HIV-infected nonprogressors.

The function of CD3+CD56+ NKT-like cells in HIV-infected individuals.

CD3+CD56+ NKT-like cells are one of the critical effectors in the immune response to viral infection and tumors, but the functional features of NKT-like cells in HIV infection have been rarely reported. In this study, we observed and described the state of NKT-like cell functions in primary HIV-infected individuals (PHIs), chronic HIV-infected individuals (CHIs), long-term nonprogressors (LTNPs), and HIV-negative controls (NCs). The results showed that the percentage of IFN-γ +CD3+CD56+ NKT-like cells was notably higher in LTNPs compared with CHIs, and the proportion of CD3+CD56+ NKT-like cells with dual function (IFN-γ +CD107a+ NKT-like cells) in LTNPs was also much higher than in CHIs. Additionally, the percentages of IFN-γ +CD107a+ NKT-like cells negatively correlated with viral load. Taken together, our data demonstrated that good functions of CD3+CD56+ NKT-like cells in LTNPs likely occurred as a protective mechanism that slows down HIV disease progression.

Recombinant Tax1 and Tax2 proteins inhibit HIV-1 replication in peripheral blood mononuclear cells

Patients with HIV-1 and HTLV-2 coinfections often exhibit a clinical course similar to HIV-1 infected long-term nonprogressors. This observation has been attributed in part to the ability of the HTLV Tax2 protein to activate production of antiviral chemokines and to downregulate the CCR5 co receptor on lymphocytes. Therefore we investigated the possibility that a recombinant Tax2 protein could suppress HIV-1 viral replication in vitro. R5-tropic HIV-1 (NLAD8)-infected-PBMCs were treated daily with recombinant Tax1 and Tax2 proteins (dosage range 1-100 pM). Culture supernatants were collected at intervals for 22 days post-infection and assayed for levels of HIV-1 p24 antigen. Treatment of PBMCs with Tax2 protein resulted in significant reduction in HIV-1 p24 antigen levels (p<0.05) at days 10, 14, and 18 post-infection compared to HIV-1-infected or mock-treated PBMCs. This was preceded by the detection of increased levels of CC-chemokines MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, on days 1-7 of infection (p<0.05). Similar, but less robust inhibition was determined in Tax1 treated PBMCs. Addition of Tax2 proteins starting 48 hours previous to infection resulted in a significant inhibition of HIV-1 p24 levels (p<0.05 at days 7 to 14 compared to the untreated, R5 infected PBMCs. In contrast, when addition of Tax2 began two days after R5 infection, significant HIV-1 p24 levels were only determined at days 7 and 10 for 1 pM and at day 7 for 10 pM (p<0.05). These results support the contention that Tax1 and Tax2 play a role in generating antiviral responses against HIV-1 in vivo and in vitro.

Higher NK Cell IFN-γ Production is Associated with Delayed HIV Disease Progression in LTNPs

Natural killer (NK) cells are important effectors of the innate immune system that help control viral infections and tumorigenesis. However, the relationship between NK cell function and HIV disease progression remains poorly defined. In this study, we examined the function of NK cells in Chinese patients who were HIV-infected but treatment-naïve. These individuals include primary HIV-infected patients (PHIs), typical progressors (TPs), and long-term nonprogressors (LTNPs). We observed an increase of CD56(dim) NK cells in PHIs, but the production of interferon-gamma (IFN-γ) and CD107a expression in PHIs were not altered compared with normal control subjects (NCs). However, the NK cells from LTNPs exhibited increased activities in IFN-γ production, CD107a expression and granzyme B change after K562 stimulation compared with NCs. Furthermore, the percentage of IFN-γ(+)CD107a(-) NK cells in LTNPs was higher than that in TPs, PHIs and NCs; levels of IFN-γ production in LTNP NK cells exhibited an inverse correlation with viral loads. Similar correlations, however, were not observed in the PHI and TP groups. Taken together, these data demonstrate that enhanced NK cell function may contribute to the control of HIV infection, and increased IFN-γ secretion may be associated with delayed disease progression.

Impact of Human Immunodeficiency Virus Infection on Measures of Cardiovascular Disease in Long-Term Nonprogressors

Background Human immunodeficiency virus (HIV)-positive patients are at increased risk of accelerated atherosclerosis and cardiovascular disease (CVD) progression. However, it remains unclear whether this is the result of antiretroviral therapy, CVD risk factors, viral infection, systemic inflammation, or a combination of these elements. This study evaluated the effects of untreated HIV on carotid intimal-medial thickening (cIMT) and serum levels of selected inflammatory markers (IMs), known measures of CVD progression. Methods A cross-sectional case-control study was performed in HIV-infected long-term nonprogressors (LTNPs), with a HIV-negative control group matched by age, race, and sex. Clinical data, lipid profile, CD4 cell counts, HIV-1 RNA levels, cIMT at 3 different locations, and serum levels of different IMs were recorded. Cardiovascular disease risk factors, cIMT, and IMs were statistically compared between the LTNP and HIV-negative groups. Results Thirty-two subjects were enrolled (16 LTNP and 16 controls), and no significant difference in CVD risk factors was found. There was significantly increased cIMT at the carotid bulb for the LTNP group (P Conclusions For the LTNPs, cIMT at the bulb and serum levels of soluble tumor necrosis factor II were significantly greater than the controls, and soluble vascular adhesion molecule-1 significantly correlated with bulb cIMT. This study emphasizes the role of viremia in promoting CVD among HIV-positive patients, likely through inducing systemic inflammation.