Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T cells on antiretroviral therapy (ART) may inform strategies for human immunodeficiency virus (HIV) cure. We investigated the role of CD4+ count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799, or ≥ 800 cells/mm3. After 36-44 months on ART, the levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA), and two-long terminal repeat HIV-DNA in CD4+ T cells were quantified and plasma HIV-RNA was measured by single-copy assay. We measured T-cell expression of Human Leucocyte Antigen-DR Isotype (HLA-DR), programmed death-1, and phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799, and 50 in the ≥ 800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA, and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥ 800 cells/mm3 at ART initiation compared with 600-799 or 500-599 cells/mm3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥ 800 vs 500-599 cells/mm3 (median [interquartile range]: 16.3 [7.0-117.6] vs 68.4 [13.7-213.1] copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females. CONCLUSIONS: Initiating ART with a CD4+ count ≥ 800 cells/mm3 compared with 600-799 or 500-599 cells/mm3 was associated with achieving a substantially smaller HIV reservoir on ART.

Effect of Stopping Cotrimoxazole Preventive Therapy on Microbial Translocation and Inflammatory Markers Among Human Immunodeficiency Virus-Infected Ugandan Adults on Antiretroviral Therapy: The COSTOP Trial Immunology Substudy.

BACKGROUND: Cotrimoxazole preventive therapy (CPT) in human immunodeficiency virus (HIV) infection is a World Health Organization-recommended standard of care in resource-limited settings, but the mechanism of CPT's beneficial effects is unclear. The COSTOP trial (ISRCTN44723643) evaluated the noninferiority of discontinuing CPT in stabilized patients on antiretroviral therapy. The COSTOP immunology substudy was conducted on a subset of COSTOP participants randomized to continue CPT (n = 86) or discontinue CPT (placebo, n = 86) as daily treatment for 1 year. METHODS: We evaluated whether CPT reduces microbial translocation, indicated by the presence of bacterial lipopolysaccharide (LPS) and LPS control factors such as soluble CD14 (sCD14) and endotoxin core antibody (EndoCAb immunoglobulin M [IgM]) in plasma. Intestinal barrier damage as indicated by plasma intestinal fatty acid binding protein (IFABP), T-cell activation, and the inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were also evaluated. RESULTS: We found no significant change in markers of microbial translocation (LPS, IFABP, sCD14, and T-cell activation), with decreased EndoCAb IgM. There was significant increase in inflammation markers (CRP and IL-6) after stopping CPT compared to those who continued CPT. CONCLUSIONS: These results add to the evidence of immunological benefits of CPT among HIV-infected populations in resource-limited settings. However, no evidence of reducing microbial translocation was observed.

Computational MHC-I epitope predictor identifies 95% of experimentally mapped HIV-1 clade A and D epitopes in a Ugandan cohort.

BACKGROUND: Identifying immunogens that induce HIV-1-specific immune responses is a lengthy process that can benefit from computational methods, which predict T-cell epitopes for various HLA types. METHODS: We tested the performance of the NetMHCpan4.0 computational neural network in re-identifying 93 T-cell epitopes that had been previously independently mapped using the whole proteome IFN-γ ELISPOT assays in 6 HLA class I typed Ugandan individuals infected with HIV-1 subtypes A1 and D. To provide a benchmark we compared the predictions for NetMHCpan4.0 to MHCflurry1.2.0 and NetCTL1.2. RESULTS: NetMHCpan4.0 performed best correctly predicting 88 of the 93 experimentally mapped epitopes for a set length of 9-mer and matched HLA class I alleles. Receiver Operator Characteristic (ROC) analysis gave an area under the curve (AUC) of 0.928. Setting NetMHCpan4.0 to predict 11-14mer length did not improve the prediction (37-79 of 93 peptides) with an inverse correlation between the number of predictions and length set. Late time point peptides were significantly stronger binders than early peptides (Wilcoxon signed rank test: p = 0.0000005). MHCflurry1.2.0 similarly predicted all but 2 of the peptides that NetMHCpan4.0 predicted and NetCTL1.2 predicted only 14 of the 93 experimental peptides. CONCLUSION: NetMHCpan4.0 class I epitope predictions covered 95% of the epitope responses identified in six HIV-1 infected individuals, and would have reduced the number of experimental confirmatory tests by > 80%. Algorithmic epitope prediction in conjunction with HLA allele frequency information can cost-effectively assist immunogen design through minimizing the experimental effort.

Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy.

BACKGROUND: Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children. METHODS: CD4(+) T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART. RESULTS: There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4(+) T-cell count ratio (calculated as the ratio of the subject's CD4(+) T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4(+) and CD8(+) T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8(+) T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died). CONCLUSIONS: While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.

Schistosoma mansoni and HIV acquisition in fishing communities of Lake Victoria, Uganda: a nested case-control study.

OBJECTIVE: It has been suggested that Schistosoma mansoni, which is endemic in African fishing communities, might increase susceptibility to human immunodeficiency virus (HIV) acquisition. If confirmed, this would be of great public health importance in these high HIV-risk communities. This study was undertaken to determine whether S. mansoni infection is a risk factor for HIV infection among the fishing communities of Lake Victoria, Uganda. We conducted a matched case-control study, nested within a prospective HIV incidence cohort, including 50 HIV seroconverters (cases) and 150 controls during 2009-2011. METHODS: S. mansoni infection prior to HIV seroconversion was determined by measuring serum circulating anodic antigen (CAA) in stored serum. HIV testing was carried out using the Determine rapid test and infection confirmed by enzyme-linked immunosorbent assays. RESULTS: About 49% of cases and 52% of controls had S. mansoni infection prior to HIV seroconversion (or at the time of a similar study visit, for controls): odds ratio, adjusting for ethnicity, religion, marital status, education, occupation, frequency of alcohol consumption in previous 3 months, number of sexual partners while drunk, duration of stay in the community, and history of schistosomiasis treatment in the past 2 years was 1.23 (95% CI 0.3-5.7) P = 0.79. S. mansoni infections were chronic (with little change in status between enrolment and HIV seroconversion), and there was no difference in median CAA concentration between cases and controls. CONCLUSIONS: These results do not support the hypothesis that S. mansoni infection promotes HIV acquisition.

Quantitative and qualitative differences in the T cell response to HIV in uninfected Ugandans exposed or unexposed to HIV-infected partners.

HIV-exposed and yet persistently uninfected individuals have been an intriguing, repeated observation in multiple studies, but uncertainty persists on the significance and implications of this in devising protective strategies against HIV. We carried out a cross-sectional analysis of exposed uninfected partners in a Ugandan cohort of heterosexual serodiscordant couples (37.5% antiretroviral therapy naive) comparing their T cell responses to HIV peptides with those of unexposed uninfected individuals. We used an objective definition of exposure and inclusion criteria, blinded ex vivo and cultured gamma interferon (IFN-γ) enzyme-linked immunospot assays, and multiparameter flow cytometry and intracellular cytokine staining to investigate the features of the HIV-specific response in exposed versus unexposed uninfected individuals. A response rate to HIV was detectable in unexposed uninfected (5.7%, 95% confidence interval [CI] = 3.3 to 8.1%) and, at a significantly higher level (12.5%, 95% CI = 9.7 to 15.4%, P = 0.0004), in exposed uninfected individuals. The response rate to Gag was significantly higher in exposed uninfected (10/50 [20.%]) compared to unexposed uninfected (1/35 [2.9%]) individuals (P = 0.0004). The magnitude of responses was also greater in exposed uninfected individuals but not statistically significant. The average number of peptide pools recognized was significantly higher in exposed uninfected subjects than in unexposed uninfected subjects (1.21 versus 0.47; P = 0.0106). The proportion of multifunctional responses was different in the two groups, with a higher proportion of single cytokine responses, mostly IFN-γ, in unexposed uninfected individuals compared to exposed uninfected individuals. Our findings demonstrate both quantitative and qualitative differences in T cell reactivity to HIV between HESN (HIV exposed seronegative) and HUSN (HIV unexposed seronegative) subject groups but do not discriminate as to whether they represent markers of exposure or of protection against HIV infection.

A Sparse and Locally Coherent Morphable Face Model for Dense Semantic Correspondence Across Heterogeneous 3D Faces.

The 3D Morphable Model (3DMM) is a powerful statistical tool for representing 3D face shapes. To build a 3DMM, a training set of face scans in full point-to-point correspondence is required, and its modeling capabilities directly depend on the variability contained in the training data. Thus, to increase the descriptive power of the 3DMM, establishing a dense correspondence across heterogeneous scans with sufficient diversity in terms of identities, ethnicities, or expressions becomes essential. In this manuscript, we present a fully automatic approach that leverages a 3DMM to transfer its dense semantic annotation across raw 3D faces, establishing a dense correspondence between them. We propose a novel formulation to learn a set of sparse deformation components with local support on the face that, together with an original non-rigid deformation algorithm, allow the 3DMM to precisely fit unseen faces and transfer its semantic annotation. We extensively experimented our approach, showing it can effectively generalize to highly diverse samples and accurately establish a dense correspondence even in presence of complex facial expressions. The accuracy of the dense registration is demonstrated by building a heterogeneous, large-scale 3DMM from more than 9,000 fully registered scans obtained by joining three large datasets together.

Automatic Estimation of Self-Reported Pain by Trajectory Analysis in the Manifold of Fixed Rank Positive Semi-Definite Matrices.

We propose an automatic method to estimate self-reported pain based on facial landmarks extracted from videos. For each video sequence, we decompose the face into four different regions and the pain intensity is measured by modeling the dynamics of facial movement using the landmarks of these regions. A formulation based on Gram matrices is used for representing the trajectory of landmarks on the Riemannian manifold of symmetric positive semi-definite matrices of fixed rank. A curve fitting algorithm is used to smooth the trajectories and temporal alignment is performed to compute the similarity between the trajectories on the manifold. A Support Vector Regression classifier is then trained to encode extracted trajectories into pain intensity levels consistent with self-reported pain intensity measurement. Finally, a late fusion of the estimation for each region is performed to obtain the final predicted pain level. The proposed approach is evaluated on two publicly available datasets, the UNBCMcMaster Shoulder Pain Archive and the Biovid Heat Pain dataset. We compared our method to the state-of-the-art on both datasets using different testing protocols, showing the competitiveness of the proposed approach.

Automatic Estimation of Self-Reported Pain by Interpretable Representations of Motion Dynamics.

We propose an automatic method for pain intensity measurement from video. For each video, pain intensity was measured using the dynamics of facial movement using 66 facial points. Gram matrices formulation was used for facial points trajectory representations on the Riemannian manifold of symmetric positive semi-definite matrices of fixed rank. Curve fitting and temporal alignment were then used to smooth the extracted trajectories. A Support Vector Regression model was then trained to encode the extracted trajectories into ten pain intensity levels consistent with the Visual Analogue Scale for pain intensity measurement. The proposed approach was evaluated using the UNBC McMaster Shoulder Pain Archive and was compared to the state-of-the-art on the same data. Using both 5-fold cross-validation and leave-one-subject-out cross-validation, our results are competitive with respect to state-of-the-art methods.

Fall Detection of Elderly People Using the Manifold of Positive Semidefinite Matrices.

Falls are one of the most critical health care risks for elderly people, being, in some adverse circumstances, an indirect cause of death. Furthermore, demographic forecasts for the future show a growing elderly population worldwide. In this context, models for automatic fall detection and prediction are of paramount relevance, especially AI applications that use ambient, sensors or computer vision. In this paper, we present an approach for fall detection using computer vision techniques. Video sequences of a person in a closed environment are used as inputs to our algorithm. In our approach, we first apply the V2V-PoseNet model to detect 2D body skeleton in every frame. Specifically, our approach involves four steps: (1) the body skeleton is detected by V2V-PoseNet in each frame; (2) joints of skeleton are first mapped into the Riemannian manifold of positive semidefinite matrices of fixed-rank 2 to build time-parameterized trajectories; (3) a temporal warping is performed on the trajectories, providing a (dis-)similarity measure between them; (4) finally, a pairwise proximity function SVM is used to classify them into fall or non-fall, incorporating the (dis-)similarity measure into the kernel function. We evaluated our approach on two publicly available datasets URFD and Charfi. The results of the proposed approach are competitive with respect to state-of-the-art methods, while only involving 2D body skeletons.

The impact of viraemia on inflammatory biomarkers and CD4+ cell subpopulations in HIV-infected children in sub-Saharan Africa.

OBJECTIVE: To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa. DESIGN: Longitudinal cohort study. METHODS: In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events. RESULTS: Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression. CONCLUSIONS: As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.

Effect of high-intensity versus low-intensity praziquantel treatment on HIV disease progression in HIV and Schistosoma mansoni co-infected patients: a randomised controlled trial.

Background: It has been hypothesised that Schistosoma co-infection exacerbates HIV progression, and hence anthelminthic intervention in co-infected individuals will delay it. We evaluated effects of high-intensity versus low-intensity praziquantel treatment of schistosomiasis on HIV disease progression among co-infected patients from fishing populations around Lake Victoria, Uganda. Methods: Between August 2012 and September 2015, we conducted an open-label randomised, controlled trial. Adults, antiretroviral therapy-naïve, CD4 counts ≥350 cells/µl, HIV and S. mansoni co-infected, were randomised 1:1 to praziquantel (40mg/kg) given quarterly (starting at enrolment) or annually (starting 12 weeks after enrolment; such that low-intensity participants were still untreated when sampled at 12 weeks). A non-randomised HIV-positive S. mansoni-negative comparison group was recruited. The primary outcome was mean change in plasma viral load at 12 and 60 weeks. Results: In total 363 participants (high-intensity 113, low-intensity 113, comparison group 137) were recruited; 96 (85.0%), 97 (85.8%) and 107 (78.1%) completed 60 weeks of follow up, respectively. Adjusting for baseline age and viral load, the geometric mean ratio (aGMR [95%CI]) viral load for high-intensity vs low-intensity groups at 12 weeks was 0.90 [0.65, 1.25] p=0.55 and at 60 weeks 1.88 [0.78, 4.53] p=0.16. Results in the comparison group were similar to trial arms. High-intensity, compared to low-intensity, treatment resulted in substantially lower S. mansoni prevalence at all follow up visits (p<0.05). Conclusions: In communities with a high burden of both S. mansoni and HIV infection, high-intensity treatment of S. mansoni does not delay HIV progression despite relevant benefit for parasite clearance. Trial registration: ISRCTN15371662 (17/11/2016).

Macrophage Inflammatory Protein-1 Beta and Interferon Gamma Responses in Ugandans with HIV-1 Acute/Early Infections.

Control of HIV replication through CD4(+) and CD8(+) T cells might be possible, but the functional and phenotypic characteristics of such cells are not defined. Among cytokines produced by T cells, CCR5 ligands, including macrophage inflammatory protein-1 beta (MIP-1ß), compete for the CCR5 coreceptor with HIV, promoting CCR5 internalization and decreasing its availability for virus binding. Interferon (IFN)-γ also has some antiviral activity and has been used as a read-out for T cell immunogenicity. We used cultured ELISpot assays to compare the relative contribution of MIP-1ß and IFN-γ to HIV-specific responses. The magnitude of responses was 1.36 times higher for MIP-1ß compared to IFN-γ. The breadth of the MIP-1ß response (45.41%) was significantly higher than IFN-γ (36.88%), with considerable overlap between the peptide pools that stimulated both MIP-1ß and IFN-γ production. Subtype A and D cross-reactive responses were observed both at stimulation and test level, but MIP-1ß and IFN-γ responses displayed different effect patterns. We conclude that the MIP-1ß ELISpot would be a useful complement to the evaluation of the immunogenicity of HIV vaccines and the activity of adjuvants.

Effect of Schistosoma mansoni Infection on Innate and HIV-1-Specific T-Cell Immune Responses in HIV-1-Infected Ugandan Fisher Folk.

In Uganda, fisher folk have HIV prevalence rates, about four times higher than the national average, and are often coinfected with Schistosoma mansoni. We hypothesized that innate immune responses and HIV-specific Th1 immune responses might be downmodulated in HIV/S. mansoni-coinfected individuals compared with HIV+/S. mansoni-negative individuals. We stimulated whole blood with innate receptor agonists and analyzed supernatant cytokines by Luminex. We evaluated HIV-specific responses by intracellular cytokine staining for IFN-γ, IL-2, and TNF-α. We found that the plasma viral load and CD4 count were similar between the HIV+SM+ and HIV+SM- individuals. In addition, the TNF-α response to the imidazoquinoline compound CL097 and ß-1, 3-glucan (curdlan), was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. The frequency of HIV-specific IFN-γ+IL-2-TNF-α- CD8 T cells and IFN-γ+IL-2-TNF-α+ CD4 T cells was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. These findings do not support the hypothesis that S. mansoni downmodulates innate or HIV-specific Th1 responses in HIV/S. mansoni-coinfected individuals.

3-D Human Action Recognition by Shape Analysis of Motion Trajectories on Riemannian Manifold.

Recognizing human actions in 3-D video sequences is an important open problem that is currently at the heart of many research domains including surveillance, natural interfaces and rehabilitation. However, the design and development of models for action recognition that are both accurate and efficient is a challenging task due to the variability of the human pose, clothing and appearance. In this paper, we propose a new framework to extract a compact representation of a human action captured through a depth sensor, and enable accurate action recognition. The proposed solution develops on fitting a human skeleton model to acquired data so as to represent the 3-D coordinates of the joints and their change over time as a trajectory in a suitable action space. Thanks to such a 3-D joint-based framework, the proposed solution is capable to capture both the shape and the dynamics of the human body, simultaneously. The action recognition problem is then formulated as the problem of computing the similarity between the shape of trajectories in a Riemannian manifold. Classification using k-nearest neighbors is finally performed on this manifold taking advantage of Riemannian geometry in the open curve shape space. Experiments are carried out on four representative benchmarks to demonstrate the potential of the proposed solution in terms of accuracy/latency for a low-latency action recognition. Comparative results with state-of-the-art methods are reported.

Epidemiology and immunology of helminth-HIV interactions.

PURPOSE OF REVIEW: Helminths and HIV-1 use multiple mechanisms to avoid or deviate immune responses, and these mechanisms may interact with important consequences for the epidemiology of each infection. In this review, we summarize recent immunological and epidemiological advances in the understanding of HIV-1-helminth co-infections. RECENT FINDINGS: Considering the extent of geographical overlap of these chronic infections, there has been so far surprisingly limited and inconsistent evidence of important interactive effects, either from epidemiological studies examining associations between helminth infection indicators and HIV disease parameters, or from studies that have dissected the immune mechanisms triggered by each pathogen in isolation and investigated their interaction. Systematic reviews have found inconsistent evidence for a beneficial effect of anthelmintic treatment of helminth-HIV-1 co-infected individuals on viral load or CD4 cell counts. It is not certain that co-infection with HIV-1 and helminths will always be more detrimental to the host than either single infection alone, or that intervening against co-infections will have only beneficial effects. SUMMARY: A consensus on the implications of co-infection on de-worming and vaccination policies has not yet emerged. Well powered randomized trials in HIV-1-infected individuals with defined helminth infections are required to determine the benefits of anthelmintic interventions.

3D face recognition using isogeodesic stripes.

In this paper, we present a novel approach to 3D face matching that shows high effectiveness in distinguishing facial differences between distinct individuals from differences induced by nonneutral expressions within the same individual. The approach takes into account geometrical information of the 3D face and encodes the relevant information into a compact representation in the form of a graph. Nodes of the graph represent equal width isogeodesic facial stripes. Arcs between pairs of nodes are labeled with descriptors, referred to as 3D Weighted Walkthroughs (3DWWs), that capture the mutual relative spatial displacement between all the pairs of points of the corresponding stripes. Face partitioning into isogeodesic stripes and 3DWWs together provide an approximate representation of local morphology of faces that exhibits smooth variations for changes induced by facial expressions. The graph-based representation permits very efficient matching for face recognition and is also suited to being employed for face identification in very large data sets with the support of appropriate index structures. The method obtained the best ranking at the SHREC 2008 contest for 3D face recognition. We present an extensive comparative evaluation of the performance with the FRGC v2.0 data set and the SHREC08 data set.

Host HLA B*allele-associated multi-clade Gag T-cell recognition correlates with slow HIV-1 disease progression in antiretroviral therapy-naïve Ugandans.

BACKGROUND: Some HIV infected individuals remain asymptomatic for protracted periods of time in the absence of antiretroviral therapy (ART). Virological control, CD4 T cell loss and HIV-specific responses are some of the key interrelated determinants of HIV-1 disease progression. In this study, possible interactions between viral load, CD4 T cell slopes, host genetics and HIV-specific IFN-gamma responses were evaluated in chronically HIV-1-infected adults. METHODOLOGY/PRINCIPAL FINDINGS: Multilevel regression modeling was used to stratify clade A or D HIV-infected individuals into disease progression groups based on CD4 T cell slopes. ELISpot assays were used to quantify the frequency and magnitude of HIV-induced IFN-gamma responses in 7 defined rapid progressors (RPs) and 14 defined slow progressors (SPs) at a single time point. HLA typing was performed using reference strand conformational analysis (RSCA). Although neither the breadth nor the magnitude of the proteome-wide HIV-specific IFN-gamma response correlated with viral load, slow disease progression was associated with over-representation of host immunogenetic protective HLA B* alleles (10 of 14 SPs compared to 0 of 7; p = 0.004, Fisher's Exact) especially B*57 and B*5801, multiclade Gag T-cell targeting (71%, 10 of 14 SPs compared to 14%, 1 of 7 RPs); p = 0.029, Fisher's Exact test and evident virological control (3.65 compared to 5.46 log10 copies/mL in SPs and RPs respectively); p<0.001, unpaired student's t-test CONCLUSIONS: These data are consistent with others that associated protection from HIV disease with inherent host HLA B allele-mediated ability to induce broader Gag T-cell targeting coupled with apparent virological control. These immunogenetic features of Gag-specific immune response which could influence disease progression may provide useful insight in future HIV vaccine design.