Rate Of HIV Disease Progression Research Articles

Pre-infection plasma cytokines and chemokines as predictors of HIV disease progression

Previous studies have highlighted the role of pre-infection systemic inflammation on HIV acquisition risk, but the extent to which it predicts disease progression outcomes is less studied. Here we examined the relationship between pre-infection plasma cytokine expression and the rate of HIV disease progression in South African women who seroconverted during the CAPRISA 004 tenofovir gel trial. Bio-Plex 200 system was used to measure the expression of 47 cytokines/chemokines in 69 seroconvertors from the CAPRISA 004 trial. Cox proportional hazards regression analyses were used to measure associations between cytokine expression and CD4 decline prior to antiretroviral therapy initiation. Linear regression models were used to assess whether pre-infection cytokine expression were predictors of disease progression outcomes including peak and set-point viral load and CD4:CD8 ratio at less and greater than180 days post infection. Several cytokines were associated with increased peak HIV viral load (including IL-16, SCGFβ, MCP-3, IL-12p40, SCF, IFNα2 and IL-2). The strongest association with peak viral load was observed for SCGFβ, which was also inversely associated with lowest CD4:CD8 ratio < 180 days post infection and faster CD4 decline below 500 cells/µl (adjusted HR 4.537, 95% CI 1.475–13.954; p = 0.008) in multivariable analysis adjusting for age, study site, contraception, baseline HSV-2 status and trial arm allocation. Our results show that pre-infection systemic immune responses could play a role in HIV disease progression, especially in the early stages of infection.

Polymorphism rs1385129 Within Glut1 Gene SLC2A1 Is Linked to Poor CD4+ T Cell Recovery in Antiretroviral-Treated HIV+ Individuals.

Untreated HIV infection is associated with progressive CD4+ T cell depletion, which is generally recovered with combination antiretroviral therapy (cART). However, a significant proportion of cART-treated individuals have poor CD4+ T cell reconstitution. We investigated associations between HIV disease progression and CD4+ T cell glucose transporter-1 (Glut1) expression. We also investigated the association between these variables and specific single nucleotide polymorphisms (SNPs) within the Glut1 regulatory gene AKT (rs1130214, rs2494732, rs1130233, and rs3730358) and in the Glut1-expressing gene SLC2A1 (rs1385129 and rs841853) and antisense RNA 1 region SLC2A1-AS1 (rs710218). High CD4+Glut1+ T cell percentage is associated with rapid CD4+ T cell decline in HIV-positive treatment-naïve individuals and poor T cell recovery in HIV-positive individuals on cART. Evidence suggests that poor CD4+ T cell recovery in treated HIV-positive individuals is linked to the homozygous genotype (GG) associated with SLC2A1 SNP rs1385129 when compared to those with a recessive allele (GA/AA) (odds ratio = 4.67; P = 0.04). Furthermore, poor response to therapy is less likely among Australian participants when compared against American participants (odds ratio: 0.12; P = 0.01) despite there being no difference in prevalence of a specific genotype for any of the SNPs analyzed between nationalities. Finally, CD4+Glut1+ T cell percentage is elevated among those with a homozygous dominant genotype for SNPs rs1385129 (GG) and rs710218 (AA) when compared to those with a recessive allele (GA/AA and AT/TT respectively) (P < 0.04). The heterozygous genotype associated with AKT SNP 1130214 (GT) had a higher CD4+Glut1+ T cell percentage when compared to the dominant homozygous genotype (GG) (P = 0.0068). The frequency of circulating CD4+Glut1+ T cells and the rs1385129 SLC2A1 SNP may predict the rate of HIV disease progression and CD4+ T cell recovery in untreated and treated infection, respectively.

T Cell Activation in South African HIV-Exposed Infants Correlates with Ochratoxin A Exposure.

The introduction of non-breastmilk foods to HIV-infected infants is associated with increased levels of immune activation, which can impact the rate of HIV disease progression. This is particularly relevant in countries where mother-to-child transmission of HIV still occurs at unacceptable levels. The goal of this study was to evaluate the levels of the toxic food contaminant ochratoxin A (OTA) in HIV-exposed South African infants that are either breastfed or consuming non-breast milk foods. OTA is a common mycotoxin, found in grains and soil, which is toxic at high doses but has immunomodulatory properties at lower doses. Samples from HIV-exposed and HIV-unexposed infants enrolled in prospective observational cohort studies were collected and analyzed at birth through 14 weeks of age. We observed that infants consuming non-breast milk foods had significantly higher plasma levels of OTA at 6 weeks of age compared to breastfed infants, increasing until 8 weeks of age. The blood levels of OTA detected were comparable to levels observed in OTA-endemic communities. OTA plasma levels correlated with HIV target cell activation (CCR5 and HLADR expression on CD4+ T cells) and plasma levels of the inflammatory cytokine CXCL10. These findings provide evidence that elevated OTA levels in South African infants are associated with the consumption of non-breastmilk foods and activation of the immune system. Reducing infant OTA exposure has the potential to reduce immune activation and provide health benefits, particularly in those infants who are HIV-exposed or HIV-infected.

Faster Adaptation in Smaller Populations: Counterintuitive Evolution of HIV during Childhood Infection.

Analysis of HIV-1 gene sequences sampled longitudinally from infected individuals can reveal the evolutionary dynamics that underlie associations between disease outcome and viral genetic diversity and divergence. Here we extend a statistical framework to estimate rates of viral molecular adaptation by considering sampling error when computing nucleotide site-frequencies. This is particularly beneficial when analyzing viral sequences from within-host viral infections if the number of sequences per time point is limited. To demonstrate the utility of this approach, we apply our method to a cohort of 24 patients infected with HIV-1 at birth. Our approach finds that viral adaptation arising from recurrent positive natural selection is associated with the rate of HIV-1 disease progression, in contrast to previous analyses of these data that found no significant association. Most surprisingly, we discover a strong negative correlation between viral population size and the rate of viral adaptation, the opposite of that predicted by standard molecular evolutionary theory. We argue that this observation is most likely due to the existence of a confounding third variable, namely variation in selective pressure among hosts. A conceptual non-linear model of virus adaptation that incorporates the two opposing effects of host immunity on the virus population can explain this counterintuitive result.

Association between Red blood cell parameters and immune status in HIV infected males

Background and Objectives: Hematologic changes have been accepted as a powerful predictor of morbidity and mortality in HIV-infected patients. It has been demonstrated that severe anemia is linked with faster rate of HIV disease progression. HIV infection affects hematological indices like MCV (Mean corpuscular volume), MCH (Mean corpuscular haemoglobin) and MCHC (Mean corpuscular hemoglobin concentration) of patients regardless of age, sex and ART. The rationale of this study was to recognize the association between RBC parameters and immune status in male HIV infected patients. Methods: The objective of this study was to consider red blood cell parameters and immune status and to contemplate the relationship between RBC indices and immune status. Results: Among the 48 HIV infected male patients, the CD4 count was significant and positively correlated with the Hemoglobin (HB) and hematocrit (PCV) values. RDW and MCHC were negatively associated but insignificant with CD4 cell count. RBC, MCV and MCH were positively associated but insignificant. CD4 cell count had a wide range with 1376 cells /cmm because of the impact of one patient whose CD4 count was 1435cells/cmm. However, the median was 290 cells /cmm indicating 50% of patients showed deteriorating CD4 cell counts. Conclusion: HIV infection affects the RBC parameters. Anemia is a significant predictor of HIV progression to AIDS. Hemoglobin concentration could be used as a consistent biomarker of the prognosis in HIV-infected patients, and that a therapeutic approach is vital for patients with anemia. There is significant association with reduced CD4 cell count and altered hemoglobin and hematocrit. Evaluation of these parameters certainly improves the condition and endurance of HIV infected patients. Keywords: HIV, CD4 cells, Hemoglobin, Hematocrit, Anemia

Combination of low producer AA-genotypes in IFN-γ and IL-10 genes makes a high risk genetic variant for HIV disease progression

Rate of HIV disease progression varies considerably among individuals, host genetic makeup be one of the possible reasons. We aimed to determine association of functional single nucleotide polymorphism (SNPs), (−179G/T and +874T/A) in IFN-γ and (−1082A/G, −819C/T and −592C/A) in IL-10 genes, with the rate of disease progression or susceptibility to HIV infection. Therapy naïve HIV infected individuals from North India, categorized as slow progressors or fast progressors and HIV exposed seronegative individuals were recruited for this study. Genotyping results revealed significantly higher frequencies of low producer AA genotype at +874T/A in IFN-γ gene and −592C/A position in IL-10 gene in FPs (p<0.002). Multifactor dimensional reduction (MDR) analysis revealed this to be a high risk combination for faster disease progression in HIV-1 infected individuals. Low producer AA genotype carriers at +874T/A in IFN-γ gene produced significantly low amounts of cellular IFN-γ. Low producing haplotype ‘ATA’ at −1082, −819 and −592 loci in IL-10 gene was significantly over-represented in FPs as compared to SPs (p<0.01) and these individuals showed poor response to therapy in terms of CD4 count gains after one year of ART, compared to high producing haplotype (GCC) carriers. Thus, a combination of genetic variations in IFN-γ and IL-10 cytokine genes in a single host associate with HIV disease progression and may help clinicians to better manage the HIV disease if known earlier.

HIV Control Decreased with Multi-Founder Infection

Why there is variation in the rate of HIV disease progression remains unclear. Recent studies have shown that between 20% and 35% of HIV-infected individuals have multiple founder variants. Might these individuals show faster disease progression? To assess this possibility, researchers used sequencing data from HIV breakthrough …

Short communication: Fc gamma receptors IIa and IIIa genetic polymorphisms do not predict HIV-1 disease progression in Kenyan women.

Genetic polymorphisms of the Fc gamma receptors (FcγR) IIa and IIIa have been implicated in the rate of HIV-1 disease progression, but results are inconsistent. We aimed to determine the association between these polymorphisms and disease progression in a cohort of HIV-1 seroconverters from Mombasa, Kenya. Neither FcγRIIa nor FcγRIIIa genotypes were predictive of set point viral load, viral load increase, CD4 decline, or HIV-1 disease progression (time to CD4 count <200 cells/mm(3), death, or treatment initiation). Our results suggest that FcγR polymorphisms might not be an important indicator of viral control and disease progression in this population.

High producer haplotype (CAG) of -863C/A, -308G/A and -238G/A polymorphisms in the promoter region of TNF-α gene associate with enhanced apoptosis of lymphocytes in HIV-1 subtype C infected individuals from North India.

IntroductionThe natural history of HIV-1 infection and its progression towards AIDS vary considerably among individuals. Host genetic factors may be one of the possible reasons for variable HIV-1 disease progression. Single nucleotide polymorphisms (SNPs) in the promoter region of TNF-α gene can influence its production. The aim of the present study was to determine the association of functional TNF-α SNPs and its associated parameters related to apoptosis that may influence the rate of HIV-1 disease progression.MethodsTherapy naive, 100 HIV slow progressors (SPs), 100 HIV fast progressors (FPs), 50 HIV exposed but seronegative individuals (ESNs) and 260 healthy controls from same ethnic origin were recruited. Genotyping of TNF-α variants (−863C/A, -308G/A and -238G/A) was done using PCR-RFLP. CD4 counts were determined by flow cytometry. Plasma viral load was estimated by COBAS AMPLICOR HIV-1 monitor test. Plasma TNF-α concentration was estimated by Human CBA Th1/Th2 cytokine kit. The lymphocyte mitochondrial membrane potential was measured by JC-1 dye by flow cytometry.ResultsGenotype and allele frequency of TNF-α -238G/A and -863C/A was not significantly different in HIV-1-infected patients when compared to controls, while that of TNF-α -308G/A variant (high TNF-α producer) was significantly higher in FPs compared to SPs (p<0.01, OR = 3.43). Haplotype analyses also showed that carriers of high TNF-α producing haplotype CAG was significantly more common among FPs compared to SPs (p<0.01, OR = 3). The circulating TNF-α levels in blood also correlated well with genotypes. The lymphocyte mitochondrial membrane potential of FPs having CAG haplotype was significantly low as compared to wild type (CGG) haplotype (417±22 vs 571±28, p<0.01).ConclusionHigh producer haplotype, CAG of TNF-α gene associates with enhanced apoptosis of lymphocytes in HIV-1 infected individuals, hence faster progression to AIDS. However, further functional studies are needed to confirm this association and this knowledge may help clinicians to better understand the disease outcome.

Rate of AIDS progression is associated with gastrointestinal dysfunction in SIV-infected pigtail macaques (P3045)

Abstract During HIV/SIV infection, mucosal immune system dysfunction and systemic immune activation are associated with progression to AIDS, however it is unclear to what extent pre-existing gastrointestinal damage relates to disease progression after infection. Pigtail macaques (PTM) are an excellent model in which to assess mucosal dysfunction in relation to HIV/SIV pathogenesis, as the majority of these animals have high levels of gastrointestinal damage, immune activation, and microbial translocation prior to infection, and rapidly progress to AIDS upon SIV infection. Here we characterized the mucosal immune environment prior to and throughout SIV infection in 13 uninfected PTM and 9 SIV-infected PTM, of which 3 were slow progressors. This small subset of slow progressors had limited innate immune activation in mucosal tissues in the periphery, which was associated with a more intact colonic epithelial barrier. Furthermore, we found that pre-infection levels of microbial translocation, as measured by lipopolysaccharide binding protein (LBP), in PTM correlated with the rate of progression to AIDS. These data suggest that pre-existing levels of microbial translocation and gastrointestinal tract dysfunction may influence the rate of HIV disease progression.

Hormonal contraceptive use and risk of HIV-1 disease progression

For HIV-1-infected women, hormonal contraception prevents unintended pregnancy, excess maternal morbidity, and vertical HIV-1 transmission. Hormonal contraceptives are widely used but their effects on HIV-1 disease progression are unclear. In a prospective study among 2269 chronically HIV-1-infected women from seven countries in eastern and southern Africa and with enrollment CD4 cell counts at least 250 cells/μl, we compared rates of HIV-1 disease progression among those using and not using hormonal contraception (i.e. oral or injectable methods). The primary outcome was a composite endpoint of CD4 decline to less than 200 cells/μl, initiation of antiretroviral therapy, or death. Three hundred and seventy-two women experienced HIV-1 disease progression during 3242 years of follow-up (incidence rate = 11.5 events per 100 person-years). Rates of HIV-1 disease progression among women who were currently using and not using hormonal contraception were 8.54 and 12.31 per 100 person-years, respectively (adjusted hazard ratio 0.74, 95% confidence interval 0.56-0.98, P = 0.04). Rates were 8.58 and 8.39 per 100 person-years for the subsets using injectable and oral contraception (adjusted hazard ratio = 0.72, P = 0.04 for injectable users and adjusted hazard ratio = 0.83, P = 0.5 for oral users compared to women not using hormonal contraception). Sensitivity analyses assessing enrollment or cumulative contraceptive use during the study demonstrated risk estimates closer to 1.0 with no evidence for accelerated disease progression. Among African women with chronic HIV-1 infection, use of hormonal contraception was not associated with deleterious consequences for HIV-1 disease progression.

HIV-1 Clade D Is Associated with Increased Rates of CD4 Decline in a Kenyan Cohort

HIV-1 is grouped phylogenetically into clades, which may impact rates of HIV-1 disease progression. Clade D infection in particular has been shown to be more pathogenic. Here we confirm in a Nairobi-based prospective female sex worker cohort (1985–2004) that Clade D (n = 54) is associated with a more rapid CD4 decline than clade A1 (n = 150, 20.6% vs 13.4% decline per year, 1.53-fold increase, p = 0.015). This was independent of “protective” HLA and country of origin (p = 0.053), which in turn were also independent predictors of the rate of CD4 decline (p = 0.026 and 0.005, respectively). These data confirm that clade D is more pathogenic than clade A1. The precise reason for this difference is currently unclear, and requires further study. This is first study to demonstrate difference in HIV-1 disease progression between clades while controlling for protective HLA alleles.

Early HLA-B*57-Restricted CD8+T Lymphocyte Responses Predict HIV-1 Disease Progression

Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57(+)) slow progressors and B57(+) rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57(+) individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57.

Marked differences in CCR5 expression and activation levels in two South African populations

The chemokine receptor CCR5 is pivotal in determining an individual's susceptibility to HIV-1 infection and rate of disease progression. To establish whether population-based differences exist in cell surface expression of CCR5 we evaluated the extent of CCR5 expression across all peripheral blood cell types in individuals from two populations, South African Africans (SAA) and South African Caucasians (SAC). Significant differences in CCR5 expression, both in number of CCR5 molecules per cell (density) and the percentage of CCR5-expressing cells, were observed between the two study groups, within all cell subsets. Most notably, the percentage of all CCR5(+) cell subsets was significantly lower in SAC compared with SAA individuals (P < 0·01) among natural killer (NK) -cell subsets (CD56(+) , CD16(+) CD56(+) and CD56(dim) ) whereas CCR5 density was significantly higher in SAC compared with SAA individuals in CCR5(+) CD8(+) T-cell subsets and CCR5(+) NK-cell subsets (CD56(+) , CD16(+) CD56(+) and CD56(dim) ) (all P < 0·05). These relationships were maintained after exclusion of CCR5Δ32 heterozygous individuals (n = 7) from the SAC dataset. The SAA individuals exhibited significantly higher cell activation levels, as measured by HLA-DR expression, than SAC individuals in CD4(+) T-cell subsets (P = 0·002) and CD56(+) NK-cell subsets (P < 0·001). This study serves to demonstrate that ethnically divergent populations show marked differences in both cell activation and CCR5 expression, which are likely to impact on both susceptibility to HIV-1 infection and the rate of HIV-1 disease progression.

HLA-G expressing Tregs inhibit bystander immune activation in HIV-1 infection (170.27)

Abstract T cells expressing the HLA class Ib molecule, HLA-G, represent an emerging non-classical population of regulatory T cells (Tregs). However, the functional role of these cells during HIV-1 infection remains unclear. Here, we performed a comprehensive investigation of HLA-G- expressing Tregs in patients with different rates of HIV-1 disease progression. Using flow cytometry, we found the proportion of HLA-G-expressing CD4 and CD8 T cells were significantly reduced in individuals with progressive HIV-1 infection (p&amp;lt;0.001 for both CD4 and CD8 T cells). Moreover, HLA-G expressing Tregs were inversely correlated with phenotypic markers of immune activation, CD38 and HLA-DR (p=0.026 for CD4 and p&amp;lt;0.005 for CD8 T cells), and positively correlated with CD4 T cell counts. Functional co-culture assays indicated that HLA-G-expressing CD4 and CD8 T cells were able to potently inhibit TCR-independent bystander activation, but only weakly inhibited TCR-dependent cytokine-secretion and proliferative properties of HIV-1-specific T cells. Furthermore, in vitro infection assay suggested HLA-G expressing Treg were more susceptible to HIV-1 infection (p=0.0039). These data indicate an important role of HLA-G+ Tregs for balancing bystander immune activation and anti-viral immune activity in HIV-1 infection, and suggest that the loss of these cells during advanced HIV-1 infection may contribute to immune dysregulation and HIV-1 disease progression.

Immunodominance of HIV-1 specific CD8+ T-cell responses is related to disease progression rate in vertically infected adolescents.

BackgroundHIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate.Methodology/Principal FindingsIn this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups.Conclusions/SignificanceTogether, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions.

Low Postseroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+Fast Progressors

CD4 expression in HIV replication is paradoxical: HIV entry requires high cell-surface CD4 densities, but replication requires CD4 down-modulation. However, is CD4 density in HIV+ patients affected over time? Do changes in CD4 density correlate with disease progression? Here, we examined the role of CD4 density for HIV disease progression by longitudinally quantifying CD4 densities on CD4+ T cells and monocytes of ART-naive HIV+ patients with different disease progression rates. This was a retrospective study. We defined three groups of HIV+ patients by their rate of CD4+ T cell loss, calculated by the time between infection and reaching a CD4 level of 200 cells/microl: fast (<7.5 years), intermediate (7.5-12 years), and slow progressors (>12 years). Mathematical modeling permitted us to determine the maximum CD4+ T cell count after HIV seroconversion (defined as "postseroconversion CD4 count") and longitudinal profiles of CD4 count and density. CD4 densities were quantified on CD4+ T cells and monocytes from these patients and from healthy individuals by flow cytometry. Fast progressors had significantly lower postseroconversion CD4 counts than other progressors. CD4 density on T cells was lower in HIV+ patients than in healthy individuals and decreased more rapidly in fast than in slow progressors. Antiretroviral therapy (ART) did not normalize CD4 density. Thus, postseroconversion CD4 counts define individual HIV disease progression rates that may help to identify patients who might benefit most from early ART. Early discrimination of slow and fast progressors suggests that critical events during primary infection define long-term outcome. A more rapid CD4 density decrease in fast progressors might contribute to progressive functional impairments of the immune response in advanced HIV infection. The lack of an effect of ART on CD4 density implies a persistent dysfunctional immune response by uncontrolled HIV infection.

NK Cells and immune activation in HIV-1 infection

Natural Killer (NK) cells have the potential to eliminate HIV-1 infected target cells and to influence the rate of HIV-1 disease progression. NK cells are, however, depleted during HIV-1 chronic infection and their functions remain diminished in individuals receiving antiretroviral therapy. Chronic immune activation may contribute to loss of NK cell functional potency in HIV-1 infection.

Meta-analysis to test the association of HIV-1 nef amino acid differences and deletions with disease progression.

Previous relatively small studies have associated particular amino acid replacements and deletions in the HIV-1 nef gene with differences in the rate of HIV disease progression. We tested more rigorously whether particular nef amino acid differences and deletions are associated with HIV disease progression. Amino acid replacements and deletions in patients' consensus sequences were investigated for 153 progressor (P), 615 long-term nonprogressor (LTNP), and 2,311 unknown progressor sequences from 582 subtype B HIV-infected patients. LTNPs had more defective nefs (interrupted by frameshifts or stop codons), but on a per-patient basis there was no excess of LTNP patients with one or more defective nef sequences compared to the Ps (P = 0.47). The high frequency of amino acid replacement at residues S(8), V(10), I(11), A(15), V(85), V(133), N(157), S(163), V(168), D(174), R(178), E(182), and R(188) in LTNPs was also seen in permuted datasets, implying that these are simply rapidly evolving residues. Permutation testing revealed that residues showing the greatest excess over expectation (A(15), V(85), N(157), S(163), V(168), D(174), R(178), and R(188)) were not significant (P = 0.77). Exploratory analysis suggested a hypothetical excess of frameshifting in the regions (9)SVIG and (118)QGYF among LTNPs. The regions V(10) and (152)KVEEA of nef were commonly deleted in LTNPs. However, permutation testing indicated that none of the regions displayed significantly excessive deletion in LTNPs. In conclusion, meta-analysis of HIV-1 nef sequences provides no clear evidence of whether defective nef sequences or particular regions of the protein play a significant role in disease progression.

Autocrine Production of β-Chemokines Protects CMV-Specific CD4+ T Cells from HIV Infection

Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1α and MIP-1β mRNA, resulting in a rapid increase in production of MIP-1α and MIP-1β after cognate antigen stimulation. Production of β-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of β-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1β contained 10 times less Gag DNA than did those which failed to produce MIP-1β. These data suggest that CD4+ T cells which produce MIP-1α and MIP-1β bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.