Control Of HIV Viremia Research Articles

Early antiretroviral therapy and its impact on natural killer cell dynamics in HIV-1 infected men who have sex with men: a cross-sectional pilot study evaluating the impact of early ART initiation on NK cell perturbation in HIV infection.

Phenotypic changes and functional impairment of natural killer (NK) cells occur early in HIV-1 infection. Antiretroviral therapy (ART) effectively restores CD4+ T cell counts and suppresses HIV-1 to undetectable levels. The role and efficacy of immediate ART initiation in mitigating NK cell aberrations remain to be elucidated comprehensively. This study hypothesized that HIV-1 infection negatively influences NK cell evolution and that early ART initiation restores these perturbations. Blood samples were collected longitudinally from five acutely HIV-1 infected men who have sex with men in Nairobi, Kenya. Participants were immediately initiated on ART after HIV-1 diagnosis. Blood samples were drawn pre-infection and at sequential bi-weekly post-infection time points. Peripheral blood mononuclear cells were stained with panel NK cells surface markers to assess HIV-induced phenotypic changes by flow cytometry. Some cells were also stimulated overnight with K562 cell line, IL-2, and IL-15 and stained for flow cytometry functionality. HIV-1 infection was associated with significant reductions in the production of IFN-γ (P = 0.0264), expression of CD69 (P = 0.0110), and expression of NK cell inhibitory receptor Siglec7 (P = 0.0418). We observed an increased NK cell degranulation (P = 0.0100) and an upregulated expression of cell exhaustion marker PD-1 (P = 0.0513) at post-infection time points. These changes mainly were restored upon immediate initiation of ART, except for Siglec7 expression, whose reduced expression persisted despite ART. Some HIV-associated changes in NK cells may persist despite the immediate initiation of ART in acute HIV-1 infections. Our findings suggest that understanding NK cell dynamics and their restoration after ART can offer insights into optimizing HIV-1 treatment and potentially slowing disease progression.IMPORTANCENatural killer (NK) cells play a crucial role in controlling of HIV-1 replication and progression to disease. Perturbations of their functionality may therefore result in deleterious disease outcomes. Previous studies have demonstrated reduced NK cell functionality in chronic HIV-1 infection that positively correlated to HIV-1 viral load. This may suggest that control of HIV-1 viremia in acute HIV-1 infection may aid in enhancing NK cell response boosting the inate immunity hence effective control of viral spread and establishment of viral reservoir. Antiretroviral therapy (ART) effectively supresses HIV-1 viremia to undectable levels and restores CD4+ T cell counts. Our study highlights the significant role of early ART initiation in mitigating NK cell disruptions caused by acute HIV-1 infection. Our results suggest that early initiation of ART could have benefits beyond suppressing viral load and restoring CD4+ T cell counts. In addition, it could boost the innate immunity necessary to control disease progression.

Activating Killer Immunoglobulin Receptors and HLA-C: a successful combination providing HIV-1 control

Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation. Overall, our findings support a crucial role of NK cells in the control of HIV-1 viremia.

Impact of the Polymorphism rs9264942 near the HLA-C Gene on HIV-1 DNA Reservoirs in Asymptomatic Chronically Infected Patients Initiating Antiviral Therapy.

Several genome-wide association studies have identified a polymorphism located 35 kb upstream of the coding region of HLA-C gene (rs9264942; termed −35 C/T) as a host factor significantly associated with the control of HIV-1 viremia in untreated patients. The potential association of this host genetic polymorphism with the viral reservoirs has never been investigated, nor the association with the viral control in response to the treatment. In this study, we assess the influence of the polymorphism −35 C/T on the outcome of virus burden in 183 antiretroviral-naïve HIV-1-infected individuals who initiated antiviral treatment (study STIR-2102), analyzing HIV-1 RNA viremia and HIV-1 DNA reservoirs. The rs9264942 genotyping was investigated retrospectively, and plasma levels of HIV-1 RNA and peripheral blood mononuclear cell- (PBMC-) associated HIV-1 DNA were compared between carriers and noncarriers of the protective allele −35 C before antiretroviral therapy (ART), one month after ART and at the end of the study (36 months). HIV-1 RNA and HIV-1 DNA levels were both variables significantly different between carriers and noncarriers of the allele −35 C before ART. HIV-1 DNA levels remained also significantly different one month posttherapy. However, this protective effect of the −35 C allele was not maintained after long-term ART.

Control of Viremia Enables Acquisition of Resting Memory B Cells with Age and Normalization of Activated B Cell Phenotypes in HIV-Infected Children.

HIV affects the function of all lymphocyte populations, including B cells. Phenotypic and functional defects of B cells in HIV-infected adults have been well characterized, but defects in children have not been studied to the same extent. We determined the proportion of B cell subsets and frequencies of Ag-specific memory B cells in peripheral blood from HIV-infected children and healthy controls, using flow cytometry and B cell ELISPOT, respectively. In addition, we measured the quantities and avidities of plasma Abs against various Ags by ELISA. We also determined plasma levels of BAFF and expression of BAFF receptors on B cells. Children with high HIV viremia had increased proportions of activated mature B cells, tissue-like memory B cells and plasmablasts, and low proportions of naive B cells when compared with community controls and children with low HIV viremia, similar to adults infected with HIV. HIV-infected groups had lower proportions of resting memory B cells than did community controls. Notably, high HIV viremia prevented the age-dependent accumulation of class-switched resting memory B cells. HIV-infected children, regardless of the level of viremia, showed lower quantities and avidities of IgG and lower frequencies of memory B cells against Expanded Program on Immunization vaccines. The HIV-infected children had an altered BAFF profile that could have affected their B cell compartment. Therefore, B cell defects in HIV-infected children are similar to those seen in HIV-infected adults. However, control of HIV viremia is associated with normalization of activated B cell subsets and allows age-dependent accumulation of resting memory B cells.

HAART and lungs: do HIV protease inhibitors impact cancer risk?

HAART and lungs: do HIV protease inhibitors impact cancer risk?

Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia.

CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcriptional signature compared to Th1 CD4+ cells but shared similar features with HIV-specific cytolytic CD8+ T cells. Furthermore, HIV-specific cytolytic CD4+ T cells showed comparable killing activity relative to HIV-specific CD8+ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+ T cells in the long-term control of HIV infection. The ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+ T cells to control the virus, while CD4+ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+ T cells. These findings are important for our understanding of HIV immunopathology.

Is ART suspension never a good idea? - Cons

In the mid ‘90s tremendous progress has marked the pharmacological approach to HIV-1 disease, resulting in the almost complete reversal of the “death sentence” that was associated with the diagnosis of HIV infection and AIDS. However, the terrific advantages of combination antiretroviral therapy (cART) are not available homogeneously on a global scale, with the number of individuals becoming infected still outscoring that of infected people starting treatment. Even restricting the analysis to those countries, including Europe, where cART is largely available, there are several considerations supporting the concept that therapy suspension could still be considered in specific settings, and not only for facing the management of accumulation of multidrug resistant viral species or therapy-related side effects. In fact, some of the most novel and exciting novelties in the field of HIV research have arisen from examples of either casual or programmed therapy suspension. In the case of the so-called “Mississippi Baby”, a newborn (from a mother with undiagnosed AIDS until the time of delivery) was treated with cART shortly after delivery; nonetheless, she became unequivocally infected, but seroreverted after a few weeks. Later, cART was suspended for unknown reasons, surprisingly resulting in the lack of virus rebound and HIV detectability by multiple testing, leading to the hypothesis that she might represent the second case of “cure” after Tymothy Ray Brown, the “Berlin patient” .I n a second example, adult French patients who started their antiretroviral regimens very early after primary HIV infection, underwent therapy suspension after a few years resulting in an unexpected high frequency of spontaneous control of HIV-1 viremia and disease progression (Post-therapy controllers, or VISCONTI cohort). The likelihood that they might represent conventional spontaneous controllers of disease progression, such as LTNP or Elite controllers, is minimal in that their genetic profile is enriched in the BW35 MHC allele that is counterselected in these categories. In summary, without these and other example of cART suspension our current understanding of the potential opportunities to tilt the balance in favor of the host rather than of the virus would be more limited and perhaps would prevent future strategic approaches to achieve long-term control of HIV infection with minimal side effects related to cART.

HLA-B*44 Is Associated with a Lower Viral Set Point and Slow CD4 Decline in a Cohort of Chinese Homosexual Men Acutely Infected with HIV-1

HLA class I alleles have been shown to have differential impacts on the viral load and the outcome of HIV-1 disease progression. In this study, HLA class I types from residents of China with acute HIV-1 infection, diagnosed between 2006 and 2011, were identified and the association between expression of individual HLA alleles and the level of the set point viral load was analyzed. A lower level of set point viral load was found to be associated with the Bw4 homozygote on HLA-B alleles. B*44 and B*57 alleles have also been found to be associated with lower set point viral load. The set point viral load of B*44-positive individuals homozygous for Bw4 was significantly lower than that of B*44-negative individuals homozygous for Bw4 (P = 0.030). The CD4 count declined to <350 in fewer B*44-positive individuals than B*44-negative individuals (X(2) = 7.295, P = 0.026). B*44-positive individuals had a lower magnitude of p24 pool-specific T cell responses than B*44-negative individuals homozygous for Bw4, though this was not statistically significant. The p24 pool-specific T cell responses were also inversely correlated with lower viral load (rs = -0.88, P = 0.033). Six peptides within p24 were recognized to induce the specific-T cell response in B*44-positive individuals, and the peptide breadth of response was same as that in B*44-negative individuals homozygous for Bw4, but the median magnitude of specific-T cell responses to the recognized peptides in B*44-positive individuals was lower than that in B*44-negative individuals homozygous for Bw4 (P = 0.049). These findings imply that weak p24-specific CD8(+) T cell responses might play an important role in the control of HIV viremia in B*44 allele-positive individuals. Such studies might contribute to the development of future therapeutic strategies that take into account the genetic background of the patients.

Exploratory clinical studies of a synthetic HIV-1 Tat epitope vaccine in asymptomatic treatment-naïve and antiretroviral-controlled HIV-1 infected subjects plus healthy uninfected subjects

TUTI-16 is a synthetic universal HIV-1 Tat epitope vaccine, designed to induce anti-Tat antibodies that block the function of circulating Tat, an HIV encoded protein secreted by HIV-1 infected cells. Circulating Tat activates CD4 T cells, permitting HIV replication and sustained viremia. Safety, immunogenicity and antiretroviral potential of TUTI-16 were explored in a randomized double-blind dose-escalating study in asymptomatic treatment-naïve HIV-1 infected subjects. TUTI-16 was safe, with mild local and systemic injection-related adverse reactions, but the antibody response was barely detectable. Surprisingly, a highly statistically significant reduction of HIV-1 viral load was found in the lowest 30 μg vaccine dose group (p < 0.01) but not at the higher doses. We posited that an anti-Tat antibody response below the limit of detection inhibited HIV viral load at this dose, an effect nullified at higher vaccine doses by activating cytokines induced by adjuvant components in TUTI-16. To clarify this immunogenicity/activation conundrum open label immunogenicity studies were performed in healthy HIV uninfected and aviremic ART-controlled HIV-infected subjects. These established that (1) healthy HIV negative subjects had robust antibody responses, maximal with 1 mg TUTI-16, (2) ART-controlled aviremic HIV infected subjects had similarly robust antibody responses, and (3) adjuvant-induced increases of HIV viral load did not occur in the presence of ART. These studies provided us a basis for the design of a protocol to explore the therapeutic potential of TUTI-16 vaccination to provide drug free control of HIV-1 viremia.

Plasmacytoid Dendritic Cells Reduce HIV Production in Elite Controllers

HIV elite controllers (EC) are a rare group of HIV-infected patients who are able to maintain undetectable viral loads during a long period of time in the absence of antiretroviral treatment. Adaptive immunity and host genetic factors, although implicated, do not entirely explain this phenomenon. On the other hand, plasmacytoid dendritic cells (pDCs) are the principal type I interferon (IFN) producers in response to viral infection, and it is unknown whether pDCs are involved in the control of HIV infection in EC. In our study, we analyzed peripheral pDC levels and IFN-α production by peripheral blood mononuclear cells (PBMCs) in EC compared to other groups of HIV-infected patients, the ability of pDCs to reduce HIV production in vitro, and the mechanisms potentially involved. We showed preserved pDC counts and IFN-α production in EC. We also observed a higher capacity of pDCs from EC to reduce HIV production and to induce T cell apoptosis, whereas pDCs from viremic patients barely responded without previous Toll-like receptor 9 (TLR-9) stimulus. The preserved functionality of pDCs from EC to reduce viral production may be one of the mechanisms involved in the control of HIV viremia in these subjects. These results demonstrate the importance of innate immunity in HIV pathogenesis, and an understanding of pDC mechanisms would be helpful for the design of new therapies.

The impact of active HIV-1 replication on the physiological age-related decline of immature-transitional B-cells in HIV-1 infected children

To characterize the level of immature-transitional B-cells in blood during pediatric HIV-1 infection in relation to active or suppressed viremia. We also aimed at characterizing the level of expression of CXCR4, CXCR5 and CCR7 on immature-transitional B-cells, as these receptors are important mediators for homing of B-cells. Forty-eight HIV-1 vertically infected children (33 viral controllers and 15 viremic patients) and 33 age-matched healthy controls were enrolled in a cross-sectional study. We measured the levels of peripheral immature-transitional B-cells in all groups in relation to switched memory B-cells by flow cytometry. In parallel we evaluated CXCR4, CXCR5 and CCR7 expression on immature-transitional B-cells and measured plasma levels of CXCL12, BAFF and interleukin-7 by ELISA. We observed a lack of physiological age-related decline of immature-transitional B-cells in viremic children in parallel to a decreased level of switched memory B-cells. Interestingly, immature-transitional B-cells from viremic children presented with high levels of CXCR4. On the contrary, the level of CXCL12, the natural ligand for CXCR4, was lowest in the HIV-1 infected group, as compared with controls. Control of HIV-1 viremia through antiretroviral treatment appears to be crucial in decreasing the expansion and alteration of immature-transitional B-cells.

Evolving spectrum and incidence of non-AIDS-defining malignancies

Non-AIDS defining cancer (NADC) has emerged as an important cause of morbidity and mortality in the HIV-infected population. Insight into the incidence, spectrum, risk factors, management, and outcome of these cancers has continued to emerge. The recent literature on this topic is reviewed. Several recent studies have explored the shifting spectrum of NADC in both developed and underdeveloped regions of the world. Investigators have shown only a minor difference in the geographic spectrum of NADC. Although several NADC have continued to occur at rates significantly higher than expected, a noticeable decline was observed in other cancers despite antiretroviral therapy. Factors other than HIV and immunosuppression proved to be important in the risk, treatment response, and outcome of these neoplasms. Studies dealing with the management of several NADC were published, including the role of highly active antiretroviral therapy (HAART). An increased overall relative risk of developing NADC continues to be reported in the HIV-infected population worldwide. The development of NADC appears to be multifactorial. Although control of HIV viremia has proven to be beneficial, the impact of HAART on NADC incidence rates and survival is not uniform. Further effort is needed to resolve the direct and indirect effects of HIV on NADC in order to guide effective prevention and treatment strategies of these malignancies.

Proteinuria in Children Infected With the Human Immunodeficiency Virus

Chaparro AI, Mitchell CD, Abitbol CL, et al. J Pediatr. 2008;152(6):844–849 PURPOSE OF THE STUDY. Proteinuria is a common feature of HIV infection and a potential complication of therapy in adult patients. This study was performed to determine the prevalence of proteinuria in a group of children infected with HIV and to assess this process over time and the impact of antiretroviral therapy on it. STUDY POPULATION. HIV-infected children (N = 286) were studied from 1998 through 2006. METHODS. Proteinuria was determined by random urine protein/creatinine ratios, with “normal” defined as &amp;lt;0.2 and “nephrotic” defined as &amp;gt;1.0. RESULTS. A total of 94 (33%) of the children had proteinuria at baseline. Of these, 32 had urine protein range ratios of ≥1.0. Clinically, the mortality rate was higher in those patients with proteinuria. It is important to note that 55 of the 94 patients with baseline proteinuria showed a good response to antiretroviral therapy, as indicated by a decrease in HIV viral load and a substantial reduction in the number of subjects who had proteinuria. CONCLUSIONS. Control of HIV viremia with antiretroviral therapy reduces progression of HIV-associated proteinuria and improves the survival rate of infected children. REVIEWER COMMENTS. Proteinuria is a common feature of HIV infection in children. Two features of this patient population may affect the generalizability of the study findings: 85% of the patients were African American or African Caribbean, and the number of individuals with complicating hepatitis B or C was not indicated. Renal disease is more prevalent in HIV-infected black people than white people, particularly with respect to HIV-associated nephropathy. Chronic viral hepatitis may also cause secondary renal disease, likely secondary to an immunocomplex-associated inflammatory process. Regardless of these caveats, the authors’ conclusion is very much warranted: “surveillance of quantitative proteinuria with imaging and chemical indicators of renal dysfunction is very much warranted” for children with HIV infection.

Despite Biased TRBV Gene Usage against a Dominant HLA B57-Restricted Epitope, TCR Diversity Can Provide Recognition of Circulating Epitope Variants

The role of epitope-specific TCR repertoire diversity in the control of HIV-1 viremia is unknown. Further analysis at the clonotype level is important for understanding the structural aspects of the HIV-1 specific repertoire that directly relate to CTL function and ability to suppress viral replication. In this study, we performed in-depth analysis of T cell clonotypes directed against a dominantly recognized HLA B57-restricted epitope (KAFSPEVIPMF; KF11) and identified common usage of the TCR beta-chain TRBV7 in eight of nine HLA B57 subjects examined, regardless of HLA B57 subtype. Despite this convergent TCR gene usage, structural and functional assays demonstrated no substantial difference in functional or structural avidity between TRBV7 and non-TRBV7 clonotypes and this epitopic peptide. In a subject where TRBV7-usage did not confer cross-reactivity against the dominant autologous sequence variant, another circulating TCR clonotype was able to preferentially recognize the variant peptide. These data demonstrate that despite selective recruitment of TCR for a conserved epitope over the course of chronic HIV-1 infection, TCR repertoire diversity may benefit the host through the ability to recognize circulating epitope variants.

Structured treatment interruptions (STIs) in HIV-1 infected pediatric populations increases interferon gamma production and reduces viremia

We assessed the effect of progressively longer antiretroviral structured treatment interruptions (STIs) starting with 3 days, increasing by 2 days in length each cycle on HIV-specific immune responses. As well, we correlated these responses with control of HIV viremia. Eight individuals became viremic and reached cycle 13 with an STI of ≥27 days. HIV-specific gamma-interferon production to inactivated HIV and vaccinia vectors expressing gag, env, nef, and pol increased (>10-fold) in six of eight subjects. Median plasma RNA levels peaked @ cycle 7 and declined to levels <10 4 cp/ml after cycle 10. In a subset of five who reached cycle 17, HIV-specific IFN-gamma frequencies increased from cycle 8 to cycle 17 with evidence of improved virologic control over comparable periods off antiretroviral therapy. This allowed us to conclude that exposure to autologous virus increased HIV-specific immune responses and decreased HIV RNA were seen in those who have had >13 interruptions, with STI intervals that exceeded 27 days.

Treatment of Acute HIV‐1 Infection: Is It Coming of Age?

The optimal time to start antiretroviral therapy for HIV-infected patients remains unknown [1-4]. Leaving public health considerations regarding transmission aside, if we are indeed able to diagnose HIV infection in patients at a very early stage, should we intervene with antiviral agents and, if so, for how long [5-7]? What is the potentially achievable long-term impact of highly active antiretroviral therapy (HAART) initiated around the time of HIV seroconversion, if such treatment is subsequently discontinued: lowering of the viral set point, preservation of CD4' T cells, a decrease in rates of disease progression, long-term control of HIV viremia, or even viral eradication [8-10]? In contrast, one may argue that very early initiation of HAART may still be provided too late to have a major impact, because virus-induced immunopathogenesis has already taken hold [11-13]. This realization would justify a more conservative treatment approach and the initiation of HAART only during chronic infection, because this approach still allows for substantial immune reconstitution in terms

HIV-1-Specific T Cell Function During Acute HIV-1 Infection

HIV-1-specific CD8+ T cells in primary infection are associated with the dramatic decline of peak viremia to the viral set point, while their antiviral activity in chronic infection is less apparent. Here, we comparatively analyzed functional properties of HIV-1-specific CD8+ T cells in primary and chronic infection, and demonstrate that the functional avidity and TCR affinity of HIV-1-specific CD8+ T cells was consistently higher in primary infection than in chronic infection. The change of TCR affinities between primary and chronic infection was linked to an almost complete switch in the clonotypic composition of epitope-specific CD8+ T cells, resulting from the preferential loss of high-avidity CD8+ T cell clones. These data suggest that the initial recruitment of high-avidity HIV-1specific CD8+ T cell may contribute to the control of HIV1 viremia during primary infection, while their selective elimination during the subsequent disease process contributes to the loss of immune control during chronic infection. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Changes in Hepatitis C Viral Response After Initiation of Highly Active Antiretroviral Therapy and Control of HIV Viremia in Chronically Co-infected Individuals

Background: HIV seropositive individuals co-infected with hepatitis C virus (HCV) have an increased risk for liver cirrhosis. We examined the long-term effect of controlling HIV infection with highly active antiretroviral therapy (HAART) on HCV viremia among co-infected patients. Method: HIV/HCV co-infected patients who initiated HAART and were able to control HIV viremia to <500 copies/mL were evaluated. HIV and HCV viremia were measured at each time point from frozen plasma samples by using bDNA methodology. Liver function tests and CD4+ and CD8+ T cell counts of all patients were obtained at each time point. Results: Seventeen co-infected patients met criteria for study from a cohort of 156 patients. Median time to achieve an HIV viral load (VL) <500 copies/mL after initiation of HAART was 28 weeks (range, 5-225 weeks). Thirteen of 17 patients had increases in HCV VL. Slope analysis of HCV VL vs. HIV VL was -0.14 (p = .0496), demonstrating a 0.14 log increase in HCV VL concomitant with control of HIV viremia. HCV viremia returned toward baseline levels in the 16 patients who maintained HIV suppression for 6 months. None cleared HCV after initiation of HAART during this time. Alkaline phosphatase, ALT, and AST levels were not significantly changed from baseline nor correlated with change in HCV VL (p > .05). Conclusion: Control of HIV viremia may result in an early increase in HCV viremia. In this study, for every 1 log decrease of HIV VL there was a 0.14 log increase of HCV VL. The exact mechanism of this flare seen with control of HIV viremia is unknown. However, HAART alone was not able to eliminate or significantly reduce the HCV viremia in this cohort of co-infected patients.

The -1030/-862-linked TNF promoter single-nucleotide polymorphisms are associated with the inability to control HIV-1 viremia.

Control of HIV-1 viremia and progression to AIDS has been associated with specific HLA genes. The tumor necrosis factor ( TNF) and the non-classical major histocompatibility (MHC) class I chain-related A ( MICA) genes are located in the genomic segment between the HLA class I and II genes and variants of both genes have been identified. We thus analyzed TNF promoter and MICA variants in a well-characterized group of HIV-1 infected individuals with different abilities to control HIV-1 viremia. In our cohort, the -1030/-862-linked TNF promoter single-nucleotide polymorphisms (SNPs), but not MICA variants, are significantly associated with lack of control of HIV-1 viremia ( P=0.03). This association is independent of those HLA-B35 alleles associated with HIV-1 disease progression with which the -862 TNF SNP has previously been independently associated. Thus, non-randomly associated genes near the TNF locus are likely involved in control of HIV-1 viremia.

Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity.

Certain HLA-B antigens have been associated with lack of progression to AIDS. HLA-B alleles can be divided into two mutually exclusive groups based on the expression of the molecular epitopes HLA-Bw4 and HLA-Bw6. Notably, in addition to its role in presenting viral peptides for immune recognition, the HLA-Bw4, but not HLA-Bw6, motif functions as a ligand for a natural killer cell inhibitory receptor (KIR). Here, we show that profound suppression of HIV-1 viremia is significantly associated with homozygosity for HLA-B alleles that share the HLA-Bw4 epitope. Furthermore, homozygosity for HLA-Bw4 alleles was also significantly associated with the ability to remain AIDS free and to maintain a normal CD4 T cell count in a second cohort of HIV-1-infected individuals with well defined dates of seroconversion. This association was independent of the presence of a mutation in CC chemokine receptor 5 (CCR5) associated with resistance to HIV-1 infection, and it was independent of the presence of HLA alleles that could potentially confound the results. We conclude that homozygosity for HLA-Bw4-bearing B alleles is associated with a significant advantage and that the HLA-Bw4 motif is important in AIDS pathogenesis.