Nonprogressive HIV-1 Infection Research Articles

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.

Higher frequencies of functional HIV-envelope-specific memory B cells are associated with nonprogressive HIV infection in Indian population.

The HIV-1-specific antibodies are being considered for prevention and therapy in HIV infection. For effective antibody response, presence of functionally competent memory B cells (MEBs) is important; however, HIV-infection is known to alter the B-cell functionality. Very limited data are available on the HIV-specific memory B-cell population in HIV-infected Indian population. In this study, the frequencies of HIV-gp140-specific MEBs were measured in individuals with nonprogressive [long-term-nonprogressors (LTNPs), N = 20] and progressive (N = 19) HIV infection using multicolor flow cytometry. The activation and functional status of these MEBs were assessed as frequencies and mean fluorescence intensity (MFI) of the CD38 and CD40 expression, respectively. The percentages of gp140 + MEBs were higher in LTNPs than seen in progressors (P = 0.0475) and associated with higher CD4 cell count (P = 0.0312, r = 0.2833). As compared with the progressors, LTNPs also showed higher functional (CD40+) gp140 + MEBs both frequencies (P < 0.0001) and CD40 MFI (P = 0.0222), whereas the frequencies (<0.0001) and the MFI (P = 0.0047) of CD38 expression was significantly lower. Higher CD4 cell counts and lower plasma viral load values were associated with higher frequencies of CD40+ gp140 + MEBs (P < 0.0001, r = 0.4962) (P = 0.0036, r = -0.4202) and lower frequencies (P = 0.0008, r = -0.4231) and CD38 expression (MFI) (P = 0.004, r = -0.3719) (P = 0.0066, r = 0.4033). Our study suggests that LTNPs have functional HIV-specific memory B-cell compartment with reduced activation that may lead to effective HIV-specific humoral immune responses contributing to their nondisease progression status. These findings would help in better understanding of the characteristics of the HIV-specific memory B-cell population in nonprogressive HIV infection.

A Nigerian adolescent with Long term Non-progressive HIV-infection: A case report

Children infected with the Human Immunodeficiency Virus (HIV) can be rapid progressors or be at the end of the spectrum of the illness as Long-term Non-progressors (LTNPs). Long term non-progressors are patients who never received Highly Active Anti-Retroviral Therapy (HAART) during the first decade of life and are maintaining good CD4+ count associated with declining HIV RNA values. The literature on paediatric patients with LTNP infection is sparse. An adolescent with HIV LTNP and likely vertical transmission of HIV is presented in this report. She presented with chronic cough, severe anaemia and dyspnea. She was wasted with bodyweight less than the 5th centile for age. She was not sexually active and had no history of blood transfusion, scarification, incisions or sharing of sharp grooming objects. The results of investigations suggested pulmonary tuberculosis and HIV infection. Her CD4 count was 42%. She was commenced on HAART and subsequently, anti-tuberculosis medications according to NTBLCP/DOTS Programme with improvement in symptoms and appreciable weight gain. Therefore routine voluntary HIV testing is recommended for all paediatric admission after consent or assent is obtained bearing in mind that a small subset of patients may fall into the LTNPs population.

Higher Baseline ADCC Responses in Chronic Nonprogressive HIV Infection Are Associated with Reduced HIV Burden in Later Course of Disease.

The importance of anti-HIV antibodies mediating antibody-dependent cell-mediated cytotoxicity (ADCC) in protective immunity against HIV is recognized recently. The purpose of this study was to measure the functional ADCC response at different stages of HIV infection in a well-defined HIV+ cohort, including 20 recently infected individuals, 30 with long-term slow-progressive, 24 with short-term slow-progressive and 32 with progressive HIV infection using a rapid fluorometric ADCC assay. The antibodies mediating ADCC were found in all disease stages. These antibodies were detectable at as early as 25 days after the estimated date of infection, however, did not influence the viral load set point probably indicating no major influence on the early course of the disease. However, the frequency and magnitude of functional ADCC responses were associated with higher CD4+T cell count and lower viral load and were significantly lower in progressors compared with other groups. The usefulness of the ADCC responses in longer viral control was assessed in a subset of participants with slowly progressing HIV infection. In these individuals, the ADCC responses observed at the visit 1 were found to be increased over time and were associated with lower plasma viral load estimated 4 to 15 years later in the disease course. Overall, the study findings confirm the role of ADCC antibodies in reducing the viral burden and also indicate the probable role of sustained functional ADCC responses in reducing the viral burden during the later period of HIV infection.

Short Communication: Nonprogressive HIV-1 Infection Is Associated with Expansion of IL-21R Expressing Class-Switched Memory B Cells.

HIV perturbs the functionality of B cells resulting in defective humoral responses. As efficient humoral immune responses are important in controlling HIV-disease progression, we characterized the memory B cell population for its subsets and their activation (CD38 expression) and functional [interleukin (IL)-21R expression] profile in individuals with nonprogressive [long-term nonprogressors (LTNPs), N = 16] and progressive HIV disease (progressors, N = 16) along with 10 HIV uninfected healthy controls (HCs). The frequencies of total memory B cells were similar in HCs and HIV-infected individuals, whereas the frequencies of unswitched memory B (UMB) cells and CD38+ UMB cells were significantly higher in progressors than LTNPs and HCs (p < .03). LTNPs showed higher frequencies of class-switched memory B (SMB) cells and IL-21R expressing SMB cells than seen in progressors (p = .019), which were similar to that seen in HCs. The %UMB cells correlated inversely (p = .0002, r = -0.6053) and %SMB cells correlated positively (p = .0005, r = 0.5804) with CD4 count. IL-21/IL-21R interaction is required for class switching of B cells and differentiation into antibody-secreting plasma cells. The higher expression of IL-21R on class SMB cells from LTNPs might be resulting in efficient plasma cell differentiation and the functional humoral immune response that might be responsible for mounting efficient antibody response against the encountered infections. The more insights in this area might be required to further understand the role of IL-21R expressing class SMB cells in HIV infection.

Polymorphisms in Toll-Like Receptors (TLRs)-7 and 9 Genes in Indian Population with Progressive and Nonprogressive HIV-1 Infection.

The polymorphisms in Toll-like receptor (TLR) 7 and 9 genes are shown to influence HIV-1 infection. We studied HIV-1-infected Indian individuals for presence and association of TLR7 and 9 gene polymorphism with different disease outcomes. Genomic DNA from 65 HIV-infected individuals (35 long-term nonprogressors and 30 progressors) and 89 uninfected healthy donors was isolated, amplified, and sequenced for the reported polymorphisms in TLR7 [Gln11Leu (A/T); rs179008] and TLR9 (1635A/G; rs352140) genes. Of these, only the reported TLR9 single-nucleotide polymorphism [SNP; p = .017, odds ratio (OR) = 0.20] and its allele A frequency (p = .038, OR = 0.41) were found to be associated with slow disease progression. Of the new SNPs observed (three TLR7 and two TLR9), the TLR7 rs2074109 G allele showed less likely association with HIV-1 acquisition (p = .019, OR = 0.27). These findings indicate that TLR7 SNP (rs2074109) could be one of the factors for predisposition to HIV-1 and TLR9 1635A/G genotype and allele might have a role in HIV-1 disease progression in Indian population.

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.

Inefficient HIV-1 trans Infection of CD4+ T Cells by Macrophages from HIV-1 Nonprogressors Is Associated with Altered Membrane Cholesterol and DC-SIGN.

ABSTRACTProfessional antigen-presenting cells (APC; myeloid dendritic cells [DC] and macrophages [MΦ]; B lymphocytes) mediate highly efficient HIV-1 infection of CD4+ T cells, termed trans infection, that could contribute to HIV-1 pathogenesis. We have previously shown that lower cholesterol content in DC and B lymphocytes is associated with a lack of HIV-1 trans infection in HIV-1-infected nonprogressors (NP). Here, we assessed whether HIV-1 trans infection mediated by another major APC, MΦ, is deficient in NP due to altered cholesterol metabolism. When comparing healthy HIV-1 seronegatives (SN), rapid progressors (PR), and NP, we found that monocyte-derived MΦ from NP did not mediate HIV-1 trans infection of autologous CD4+ T cells, in contrast to efficient trans infection mediated by SN and PR MΦ. MΦ trans infection efficiency was directly associated with the number of DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-expressing MΦ. Significantly fewer NP MΦ expressed DC-SIGN. Unesterified (free) cholesterol in MΦ cell membranes and lipid rafting was significantly lower in NP than PR, as was virus internalization in early endosomes. Furthermore, simvastatin (SIMV) decreased the subpopulation of DC-SIGN+ MΦ as well as cis and trans infection. Notably, SIMV decreased cell membrane cholesterol and led to lipid raft dissociation, effectively mimicking the incompetent APC trans infection environment characteristic of NP. Our data support that DC-SIGN and membrane cholesterol are central to MΦ trans infection, and a lack of these limits HIV-1 disease progression. Targeting the ability of MΦ to drive HIV-1 dissemination in trans could enhance HIV-1 therapeutic strategies.IMPORTANCE Despite the success of combination antiretroviral therapy, neither a vaccine nor a cure for HIV infection has been developed, demonstrating a need for novel prophylactic and therapeutic strategies. Here, we show that efficiency of MΦ-mediated HIV trans infection of CD4+ T cells is a unique characteristic associated with control of disease progression, and it is impaired in HIV-infected NP. In vitro treatment of MΦ from healthy donors with SIMV lowers their cholesterol content, which results in a strongly reduced trans infection ability, similar to the levels of MΦ from NP. Taken together, our data support the hypothesis that MΦ-mediated HIV-1 trans infection plays a role in HIV infection and disease progression and demonstrate that the use of SIMV to decrease this mechanism of virus transfer should be considered for future HIV therapeutic development.

CD1d-Restricted Natural Killer T Cells Are Preserved in Indian Long-Term Nonprogressors.

Natural killer T (NKT) cells act as a bridge between innate and adaptive immune responses. Limited information is available regarding the role of NKT cells in the HIV disease progression especially HIV-1 C infection. NKT cells were characterized for their frequency and the activation, aging, exhaustion status, and their proliferation ability in 32 long-term nonprogressors (LTNPs), 40 progressors, 18 patients before and after suppressive combination antiretroviral therapy (cART) along with 35 HIV-1-negative subjects using multicolor flow cytometry. The frequencies of total NKT cells and their subpopulation were significantly higher in LTNPs as compared with those obtained in progressors (P < 0.0001) and were significantly associated with higher CD4 counts and with lower plasma viral loads. The percentage of activated, aged, and exhausted NKT cells were significantly lower in LTNPs as compared with the progressors and inversely correlated with CD4 count and positively with plasma viral loads. The NKT cells from the LTNPs showed higher proliferation ability. The frequency and proliferation ability of the NKT cells were partially restored after 12 months of suppressive cART but still lower than the levels in LTNPs. The degree of restoration after cART was similar in both CD4 and CD4 NKT cells. The findings demonstrate significant association of preserved NKT cells with the nonprogressive HIV infection and also showed that exhausted NKT cells are associated with disease progression. Further characterization of their functionality and assessment of sustenance in HIV infection will help to understand the HIV pathogenesis and to develop immune therapies.

Plasma concentrations of transforming growth factor beta 1 in non-progressive HIV-1 infection correlates with markers of disease progression

The human immunodeficiency virus (HIV) infection shows variable rate of disease progression. The underlying biological and molecular mechanisms involved in determining progression of HIV infection are not fully understood. The aims of this study were to determine plasma concentrations of active TGF β 1, Th1 and Th2 cytokines in patients with non-progressive and those with progressive HIV-1 infection, as well as to determine if there is an association of these cytokines to disease progression. In a cross-sectional study of 61 HIV-1 infected individuals categorized according to disease progression as having non-progressive HIV-1 infection (n=14) and progressive infection (n=47), plasma levels of active TGF β 1, INF-γ, TNF-α, IL-10, IL-1β, IL-12p70 and IL-13 were compared with HIV uninfected healthy controls (n=12). Plasma concentration of these cytokines was measured using a highly sensitive luminex200 XMAP assay. Pearson correlation test was used to assess the correlation of cytokines with CD4+ and CD8+ T cells, CD4:CD8 ratio and plasma HIV-1 RNA in the different study groups. Plasma concentrations of TGF β 1 and IL-10 were significantly decreased while IL-1β, IL-12p70 and TNF-α were increased in patients with non-progressive HIV-1 infection compared to patients with progressive infection. Plasma levels of TGF β 1 and IL-10 showed an inverse correlation with CD8+ T cell counts and CD4:CD8 ratios in patients with non-progressive HIV-1 infection, while plasma HIV-1 RNA positively correlated with CD4+ T cell counts. Plasma levels of TNF-α, IL-1β, IL-12p70 and IL-13 positively correlated with CD4+ T cell counts and inversely correlated with plasma HIV-1 RNA, CD8+ T cell count and CD4:CD8 ratio in patients with non-progressive infection. The correlation of cytokines to the state of T-lymphocyte and plasma HIV-1 RNA found in this study may provide insight into the role of cytokines in both progressive and non-progressive HIV-1 infection. Additionally, these findings may have implications for systemic cytokine-based therapies in HIV-1 infection.

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.

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.

Cellular interplay among Th17, Th1, and Treg cells in HIV‐1 subtype “C” infection

CD4 T cell depletion is central to HIV pathogenesis and disease progression. Different subsets of CD4 T cells cooperate to combat an infection. Therefore, the immune balance among Th17, Th1, and Treg cells may be critical in HIV immunopathogenesis which is not adequately defined yet. The impact of HIV-1 infection on the interplay of Th17/Th1/Treg cells in HIV-1 infected Indian individuals was examined in the present study and report that HIV-1 Gag specific peripheral blood Th17 cells were significantly depleted in late infected subjects, compared to early infected subjects and slow progressors. Although, the gradual loss of Th1 cells was also reported during HIV-1 disease progression but relative to Th17 cells, Th1 cells were found to be more resistant to HIV-1 infection. Additionally, a significant and progressive gain in Treg cellular frequency was observed as disease progress from early to late stage of HIV-1 infection. This study also indicate that slow progressors might have an intrinsic capacity to develop strong HIV-1 specific Th17 and Th1 cell responses contrasted with a faint Treg cellular performance signifies the importance of these cellular subsets in progressive versus nonprogressive HIV-1 infection. A significant gradual loss of Th17/Treg ratio was found to be associated with disease state, plasma viral load and immune activation.

Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection

About 2-5% of HIV-1-infected subjects, defined as long-term non-progressors (LTNPs), remain immunologically stable for a long time without treatment. The factors governing this condition are known only in part, and include genetic factors. Thus, we studied 20 polymorphisms of 15 genes encoding proinflammatory and immunoregulatory cytokines, chemokines and their receptors, genes involved in apoptosis, and the gene HCP5. We analyzed 47 Caucasian LTNPs infected for >9 years, compared with 131 HIV-1-infected Caucasian patients defined as 'usual progressors'. The genotypes were determined by methods based upon PCR, and the statistical analysis was performed by univariate logistic regression. The well-known CCR5Δ32 del32 allele, the cell death-related TNF-α-238 A and PDCD1-7209 T alleles, and HCP5 rs2395029 G, a non-coding protein associated with the HLA-B*5701, were found positively associated with the LTNP condition. No association was observed for other single nucleotide polymorphisms (SDF-1-801, IL-10-592, MCP-1-2518, CX3CR1 V249I, CCR2V64I, RANTES-403, IL-2-330, IL-1β-511, IL-4-590, FASL IVS3nt-169, FAS-670, FAS-1377, FASL IVS2nt-124, PDCD1-7146, MMP-7-181, and MMP7-153). The novel genetic associations between allelic variants of genes TNF-α-238 and PDCD1-7209 with the LTNP condition underline the importance of host genetic factors in the progression of HIV-1 infection and in immunological preservation.

The quest for a T cell-based immune correlate of protection against HIV: a story of trials and errors

Even before the partial success of a preventive HIV vaccine in a recent Phase III clinical trial, there had been an active research effort to determine one or more immune correlates of protection for HIV infection. This effort has been hampered by the lack of natural protective immunity against HIV. As a result, most of the studies have focused on long-term non-progressive infection or other clinical situations, none of which fully recapitulates protective immunity against HIV. Although this effort has been successful in defining characteristics of T cells in acute and non-progressive HIV infection, and has therefore greatly expanded our knowledge of the immunopathogenesis of AIDS, its success in defining immune correlates of protection is less clear. In this Opinion article we offer a perspective on how successful this effort has been in defining immune correlates of protection that have been, or will be, of use in the development of an HIV vaccine. Our view is that investing in an iterative approach to human vaccine efficacy trials of sufficient size and sampling frequency will improve the likelihood that an immune correlate of vaccine protection will be defined.

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

Several vaccination trials are evaluating the modified vaccinia virus Ankara (MVA) as a delivery vector in various clinical settings. In this paper, we present the reevaluation of a therapeutic vaccination trial in human immunodeficiency virus (HIV)-1-infected individuals treated with highly active antiretroviral therapy using MVA-expressing HIV-1 nef. Immunogenicity of MVA-nef was assessed using multicolor flow cytometry. Vaccine-induced polyfunctionality and proliferative capacity, which are associated with nonprogressive HIV-1 infection, were detectable by combining two immune assays. By means of short-term polychromatic intracellular cytokine staining, we observed a significant increase in polyfunctional Nef-specific CD4 T cells expressing interferon-γ, interleukin (IL)-2 and CD154 after vaccination, whereas changes in the quality of CD8 T-cell response could not be observed. Only the additional use of a long-term polychromatic Carboxyfluorescein succinimidyl ester (CFSE)-based proliferation assay revealed vaccine-induced Nef-specific CD8, as well as CD4 T cells with proliferative capacity. The correlation between vaccine-induced IL-2 production by CD4 T cells and the increase in proliferating Nef-specific CD8 T cells suggests a causal link between these two functions. These results highlight the importance of combining sophisticated immunomonitoring tools to unravel concealed effects of immunological interventions and support the use of the poxvirus-derived MVA vector to stimulate highly functional HIV-1-specific T-cell responses. However, the clinical benefit of these functional T cells remains to be determined.

More than ten years without any detectable HIV viremia: exceptionally long-term non-progressive HIV infection

Background It is still unclear whether the virological-immunological steady-state observed among the small number of HIVinfected patients defined “long-term non-progressors” may have a prolonged-undefined duration, or it simply represents the extremity of a gaussian curve, and the progression of HIV disease is therefore an unavoidable event. These subjects are actively investigated, to understand this prolonged infection latency, so that many studies focused on the viremia levels predictive of disease progression.

The relationship between antibody to R7V and progression of HIV type 1 infection.

The presence of antibody to R7V (anti-R7VAb), a seven-amino acid sequence derived from beta(2)-microglobulin incorporated into HIV-1 virions from the surface of infected cells, has been proposed as an early marker of nonprogressive HIV-1 infection. The present study was undertaken because no prospective studies have tested this hypothesis. Stored samples collected prospectively from 361 HIV-1 seroconverting men in the Multicenter AIDS Cohort Study (0.44-1.53 years after seroconversion) were assayed for the presence or absence of anti-R7VAb, using a standardized ELISA. Using Cox proportional hazards models, crude and adjusted relative hazards (RH) were determined for the following outcomes: (a) clinically defined AIDS, (b) clinically defined AIDS or CD4 T cell count of <200 cells/microl, and (c) death. A total of 143 (39.6%) men had early anti-R7VAb and 218 (60.4%) did not; 192 (53.2%) developed AIDS. At the visit tested, men with anti-R7VAb had significantly lower CD4 T cell counts and higher plasma HIV-1 viral loads than those without antibody. After adjustment for CD4 T cell count, HIV-1 viral load, CCR5 polymorphism, and use of combined antiretroviral therapy, the presence of anti-R7VAb was associated with a higher risk of progression for all outcomes, but not significantly so. Absence of anti-R7VAb was significantly associated with expression of HLA-B*5701 and -B*2705, two alleles associated with slower progression of HIV-1 disease. The early presence of anti-R7VAb in HIV-1 seroconverters was not associated with slower progression of HIV-1 disease.

Nef-specific CD45RA+ CD8+ T cells secreting MIP-1β but not IFN-γ are associated with nonprogressive HIV-1 infection

BackgroundLong-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease.ResultsWe analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.ConclusionThe novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.