Immune activation during chronic HIV infection is a strong clinical predictor of death and may mediate CD4+ T cell depletion. Regulatory T cells (Tregs) are CD4+CD25brightCD62Lhigh cells that actively down-regulate immune responses. We asked whether loss of Tregs during HIV infection mediates immune activation in a cross-sectional study of 81 HIV-positive Ugandan volunteers. We found that Treg number is strongly correlated with both CD4+ and CD8+ T cell activation. In multivariate modeling, this relationship between Treg depletion and CD4+ T cell activation was stronger than any other clinical factor examined, including viral load and absolute CD4 count. Tregs appear to decline at different rates compared with other CD4+ T cells, resulting in an increased regulator to helper ratio in many patients with advanced disease. We hypothesize that this skewing may contribute to T cell effector dysfunction. Our findings suggest Tregs are a major contributor to the immune activation observed during chronic HIV infection.

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Immune activation is thought to play a major role in the pathogenesis of human immunodeficiency virus (HIV). This effect may be particularly relevant in Africa, where endemic coinfections may contribute to disease progression, perhaps as a consequence of enhanced immune activation. We investigated the expression of CD38 and human leukocyte antigen (HLA)-DR on T cells in 168 HIV-seropositive volunteers in Uganda. We observed higher levels of CD4(+) and CD8(+) T cell activation in Uganda, compared with those reported in previous studies from Western countries. Coexpression of CD38 and HLA-DR on both CD4(+) and CD8(+) T cell subsets was directly correlated with viral load and inversely correlated with CD4(+) T cell counts. In antiretroviral therapy (ART)-naive volunteers, viral load and CD4(+) T cell count had stronger associations with CD8(+) and CD4(+) T cell activation, respectively. Virus suppression by ART was associated with a reduction in T cell activation, with a stronger observed effect on reducing CD8(+) compared with CD4(+) T cell activation. The presence of coinfection was associated with increased CD4(+) T cell activation but, interestingly, not with increased CD8(+) T cell activation. Our results suggest that distinct mechanisms differentially drive activation in CD4(+) and CD8(+) T cell subsets, which may impact the clinical prognostic values of T cell activation in HIV infection.

IL-10-producing T cells have been shown to inhibit Ag-specific CD8+ T cell responses, and may play a role in the immune dysregulation observed in HIV-1 infection. We characterized the Gag-specific IL-10 responses by CD8+ T cells in HIV-1-positive volunteers from Uganda. HIV-specific IL-10 responses were detected in 32 of 61 (52.4%) antiretroviral naive and 2 of 15 (13.3%) volunteers with a complete virologic response on antiretroviral therapy (< 400 copies/ml). The frequency of HIV-specific IL-10-positive cells was significantly higher in volunteers with advanced disease (CD4+ T cell count <200 cells/mm3; p = 0.0004), and correlated positively with plasma HIV RNA (r = 0.43, p = 0.0004). Interestingly, the frequency of Gag-specific CD107a/b-, but not IFN-γ-, positive cells was significantly lower in individuals with detectable IL-10-positive CD8+ T cells (p = 0.004). Gag-specific IL-10-positive CD8+ T cells demonstrated a pattern of surface memory marker expression that is distinct compared with CD107a/b- and IFN-γ-positive CD8+ T cell populations (p < 0.0001). Our study describes a distinct population of IL-10-positive CD8+ T cells that may play a role in HIV-associated immune dysfunction.

Impaired virus-specific immune responses have previously been observed with Schistosoma mansoni coinfection. We characterized Gag-specific responses in HIV-1-positive Ugandans with and without S. mansoni coinfection. We observed no significant difference in the frequency of IFN-γ CD8+ T cells between the two groups. Interestingly, expression of CD107, a marker for cytolytic activity, was significantly lower in volunteers with S. mansoni coinfection compared with those with HIV-1 infection alone (p = 0.002). In contrast, the frequency of IL-10-positive Gag-specific CD8+ T cell responses was higher in volunteers with S. mansoni coinfection (p = 0.004). Analysis of human CMV-specific CD8+ T cell responses in the same individuals failed to reveal a similar pattern of altered CD107 and IL-10 expression. Our results suggest that S. mansoni coinfection is associated with decreased Gag-specific CD8+ cytolytic T cell responses and increased number of Gag-specific IL-10 positive CD8+ T cells. Our findings may have important implications toward the implementation of HIV preventive and therapeutic programs in Africa.

BackgroundGlobal HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identifiedworldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015. MethodsWe assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data was collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses conducted for four time periods (1990-99, 2000-04, 2005-09 and 2010-15). The distribution of circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, number CRD42017067164.

Background The prevalence of Plasmodium falciparum and Intestinal Parasitic Infections (IPIs) - with the corresponding pathogenesis among children remain uncertain. This study aimed at determining the prevalence and the outcomes (including anaemia) of the respective infections and co-infections. Anaemia is a condition in which the number of red blood cells transporting oxygen to the various body parts is not sufficient to meet the needs of the body. Methods This was a cross sectional study conducted among 476-refugee camp school children. Kato-Katz technique was used to screen stool samples for intestinal parasites. Microscopy was used for malaria testing while the portable Haemoglobin (Hb) calorimeter was used to measure haemoglobin concentration. Results The overall prevalence of the mixed infections was 63.03%. Plasmodium falciparum was most prevalent of the single infections 262(55.04%) followed by Taenia spp. 14 (2.9%), Schistosoma mansoni 12(2.5%), Giardia lamblia 7 (2.9%), Trichuris trichiura 2(0.4%), Hookworm 2(0.4%) and Strongyloides stercoralis 1(0.2%). The odds of developing simple or uncomplicated malaria infection or anaemia was 14 times higher in individuals with dual co-infection with Plasmodium falciparum + Taenia sp. compared to single parasitic infection (Odds = 14.13, P = 0.019). Co-infection with Plasmodium falciparum + Taenia spp, was a strong predictor of Malaria and anaemia. Conclusion This study shows that Plasmodium falciparum and Taenia spp. co-infections is a stronger predictor of malaria and anaemia. The prevalence of malaria and anaemia remains higher than the other regions in Uganda outside restricted settlements. The findings of this study underline the need for pragmatic intervention programmes to reduce burden of the co-infections in the study area and similar settlements. Electronic supplementary material The online version of this article (10.1186/s12879-019-3939-x) contains supplementary material, which is available to authorized users.

Human immunodeficiency virus (HIV) or AIDS is currently the leading cause of death in Uganda, with at least three HIV clades (subtypes) accounting for most new infections. Whether an effective vaccine formulated on viruses from a single clade will be able to protect against infection from other local clades remains unresolved. We examined the T-cell immune responses from a cohort of HIV-seropositive individuals in Uganda with predominantly clade A and D infections. Surprisingly, we observed similar frequencies of cross-clade T-cell responses to the gag, env, and nef regions. Our data suggest that the level of viral sequence variability between distinct HIV strains does not predict the degree of cross-clade responses. High sequence homologies were also observed between consensus peptides and sequences from viral isolates, supporting the use of consensus amino acid sequences to identify immunogenic regions in studies of large populations.Human immunodeficiency virus (HIV) or AIDS continues to be the leading cause of death in sub-Saharan Africa. Although there is a critical need for an effective HIV vaccine, the undefined correlates of protective immunity in HIV type 1 (HIV-1) infection remain an important obstacle. Nevertheless, a wealth of evidence suggests that a robust cellular immune response may curtail viral replication; therefore, HIV vaccine designs have, to date, focused on eliciting strong cellular immune responses.T-cell epitope recognition is dependent on the individual class I human leukocyte antigen (HLA) alleles. The pattern of antigen recognition and immunodominance may be driven by the prevalence of these alleles in the studied population (19). The identification of highly immunogenic and conserved regions is also complicated by HIV sequence diversity (8). T-cell responses against HIV can, in turn, influence the HIV populations in generating immune escape viral variants (33).There is comprehensive data on T-cell epitopes for HIVinfected individuals of Caucasian descent. However, there is a relative paucity of information for the geographic regions where the HIV epidemic is spreading the fastest at this time, particularly sub-Saharan Africa (1,2,7,34,35). In Uganda, clades A and D (as well as A/D recombinant strains) are responsible for approximately 95% of HIV-1 infections (3,11,22,23). Previous studies of HIV-1-specific cellular immune responses in small cohorts of HIV-infected individuals and vaccine recipients in Uganda have shown cross-clade immune recognition (5, 6, 31). Nevertheless, the issue of whether an effective vaccine formulated on viruses from a single clade could protect equally well against viruses from other local clades remains unresolved.We evaluated the pattern of T-cell antigen recognition in the context of the HLA alleles and multiple circulating HIV subtypes in a cross-sectional study of HIV-infected Ugandan adults. We investigated factors that determine cross-clade Tcell recognition in the context of vaccine design for Uganda and sub-Saharan Africa. MATERIALS AND METHODS St...