HIV-2 mediated effects on target and bystander cells induce plasma proteome remodeling.

Despite low or undetectable plasma viral load, people living with HIV-2 (PLWH2) typically progress toward AIDS. The driving forces behind HIV-2 disease progression and the role of viremia are still not known, but low-level replication in tissues is believed to play a role. To investigate the impact of viremic and aviremic HIV-2 infection on target and bystander cell pathology, we used data-independent acquisition mass spectrometry to determine plasma signatures of tissue and cell type engagement. Proteins derived from target and bystander cells in multiple tissues, such as the gastrointestinal tract and brain, were detected at elevated levels in plasma of PLWH2, compared with HIV negative controls. Moreover, viremic HIV-2 infection appeared to induce enhanced release of proteins from a broader range of tissues compared to aviremic HIV-2 infection. This study expands the knowledge on the link between plasma proteome remodeling and the pathological cell engagement in tissues during HIV-2 infection.

Intra-Patient Evolution of HIV-2 Molecular Properties.

Limited data are available on the pathogenesis of HIV-2, and the evolution of Env molecular properties during disease progression is not fully elucidated. We investigated the intra-patient evolution of molecular properties of HIV-2 Env regions (V1-C3) during the asymptomatic, treatment-naïve phase of the infection in 16 study participants, stratified into faster or slower progressors. Most notably, the rate of change in the number of potential N-linked glycosylation sites (PNGS) within the Env (V1-C3) regions differed between progressor groups. With declining CD4+ T-cell levels, slower progressors showed, on average, a decrease in the number of PNGSs, while faster progressors showed no significant change. Furthermore, diversity increased significantly with time in faster progressors, whereas no such change was observed in slower progressors. No differences were identified between the progressor groups in the evolution of length or charge of the analyzed Env regions. Predicted virus CXCR4 use was rare and did not emerge as a dominating viral population during the studied disease course (median 7.9 years, interquartile range [IQR]: 5.2-14.0) in either progressor groups. Further work building on our observations may explain molecular hallmarks of HIV-2 disease progression and differences in pathogenesis between HIV-1 and HIV-2.

Hierarchical Clustering and Trajectory Analyses Reveal Viremia-Independent B-Cell Perturbations in HIV-2 Infection.

Time to AIDS in HIV-2 infection is approximately twice as long compared to in HIV-1 infection. Despite reduced viremia, HIV-2-infected individuals display signs of chronic immune activation. In HIV-1-infected individuals, B-cell hyperactivation is driven by continuous antigen exposure. However, the contribution of viremia to B-cell perturbations in HIV-2-infected individuals remains largely unexplored. Here, we used polychromatic flow cytometry, consensus hierarchical clustering and pseudotime trajectory inference to characterize B-cells in HIV-1- or HIV-2-infected and in HIV seronegative individuals. We observed increased frequencies of clusters containing hyperactivated T-bethighCD95highCD27int and proliferating T-bet+CD95highCD27+CD71+ memory B-cells in viremic HIV-1 (p < 0.001 and p < 0.001, respectively), viremic HIV-2 (p < 0.001 and p = 0.014, respectively) and in treatment-naïve aviremic HIV-2 (p = 0.004 and p = 0.020, respectively)-infected individuals, compared to seronegative individuals. In contrast, these expansions were not observed in successfully treated HIV-1-infected individuals. Finally, pseudotime trajectory inference showed that T-bet-expressing hyperactivated and proliferating memory B-cell populations were located at the terminal end of two trajectories, in both HIV-1 and HIV-2 infections. As the treatment-naïve aviremic HIV-2-infected individuals, but not the successfully ART-treated HIV-1-infected individuals, showed B-cell perturbations, our data suggest that aviremic HIV-2-infected individuals would also benefit from antiretroviral treatment.

Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals.

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DRint/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1high, TIGIThigh) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.

Cross-Reactive Antibodies With the Capacity to Mediate HIV-1 Envelope Glycoprotein-Targeted Antibody-Dependent Cellular Cytotoxicity Identified in HIV-2-Infected Individuals.

Disease progression of human immunodeficiency virus type 1 (HIV-1) is delayed by HIV type 2 (HIV-2) in individuals with dual HIV-1/HIV-2 infection. The protective mechanisms, however, are still to be revealed. In the current study we examined type-specific and cross-reactive antibody-dependent cellular cytotoxicity (ADCC) in HIV-1 and HIV-2 monoinfection or dual infection. Of note, intertype cross-reactive antibodies that mediated HIV-1 envelope glycoprotein (Env)-targeted ADCC were frequently identified in HIV-2-infected individuals. Furthermore, the magnitude of HIV-1 cross-reactive ADCC activity during HIV-2 infections depended on the HIV-1 Env origin and was associated with the duration of infection. These results suggest that preexisting antibodies against HIV-2, which mediate intertype ADCC, might contribute to control of HIV-1 during dual infection.

Low Postseroconversion CD4+ T-cell Level Is Associated with Faster Disease Progression and Higher Viral Evolutionary Rate in HIV-2 Infection.

A positive correlation between virus evolutionary rate and disease progression has been shown for human immunodeficiency virus type 1 (HIV-1) infection. Much less is known about HIV-2, the second causative agent of AIDS. We analyzed 528 HIV-2 env V1-C3 sequences generated from longitudinal plasma samples that were collected from 16 study participants during a median observation time of 7.9 years (interquartile range [IQR], 5.2 to 14.0 years). Study participants were classified as faster or slower disease progressors based on longitudinal CD4+ T-cell data. The HIV-2 evolutionary rate was significantly associated with CD4+ T-cell levels and was almost twice as high among the faster progressors as among the slower progressors. Higher evolutionary rates were accounted for by both synonymous and nonsynonymous nucleotide substitutions. Moreover, slow disease progression was associated with stronger positive selection on HIV-2/SIVsm (simian immunodeficiency virus infecting sooty mangabey) surface-exposed conserved residues. This study demonstrated a number of previously unknown characteristics linking HIV-2 disease progression with virus evolution. Some of these findings distinguish HIV-2 from HIV-1 and may contribute to the understanding of differences in pathogenesis.IMPORTANCE The relationship between HIV evolution and disease progression is fundamental to our understanding of HIV immune control and vaccine design. There are no clear definitions for faster and slower HIV-2 disease progression and for the relationship of the rate of progression with HIV-2 evolution. To address the hypothesis that viral evolution is correlated with disease progression in HIV-2 infection, we determined faster and slower disease progression based on follow-up data from a prospective cohort of police officers in Guinea-Bissau. The analysis showed that although the CD4+ T-cell level and the decline in the level were independently associated with progression to AIDS, only the CD4+ T-cell level or a combined CD4+ T-cell level/decline stratification was associated with the rate of HIV-2 evolution. The HIV-2 evolutionary rate was almost twice as high among the faster progressors as among the slower progressors. Importantly, this report defines previously unknown characteristics linking HIV-2 disease progression with virus evolution.

Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau: a prospective open cohort study.

BACKGROUND: HIV type 2 (HIV-2) is considered more benign and has fewer pathogenic consequences than HIV type 1 (HIV-1) for most infected individuals. However, reliable estimates of time to AIDS and mortality among those with HIV-2 infection are absent. We therefore aimed to compare the time to AIDS and mortality, and the CD4 T-cell dynamics between those infected with HIV-1 and HIV-2. METHODS: We did a prospective open cohort study. We included all police officers with regular employment from police stations in both urban and rural areas of Guinea-Bissau since Feb 6, 1990. We continued to include participants until Sept 28, 2009, and follow-up of HIV-1-positive and HIV-2-positive individuals continued until Sept 28, 2013. We collected blood samples at enrolment and at scheduled annual follow-up visits at police stations. We analysed longitudinal data from individuals infected with HIV-1 and HIV-2 according to time to AIDS, time to death, and T-cell dynamics. Time of HIV infection was estimated as the mid-timepoint between last HIV-seronegative and first HIV-seropositive sample. Data from an additional 2984 HIV-uninfected individuals from the same population were analysed to assess the effect of natural mortality on HIV-related mortality. FINDINGS: 872 participants tested HIV positive during the 23-year study period: 408 were infected with HIV-1 (183 infected before and 225 infected after enrolment) and 464 were infected with HIV-2 (377 before and 87 after enrolment). The median time from HIV infection to development of AIDS was 6·2 years (95% CI 5·4-7·1) for HIV-1 infection and 14·3 years (10·7-18·0) for HIV-2 infection (p<0·0001). The median survival time after HIV infection was 8·2 years (95% CI 7·5-8·9) for HIV-1 infection and 15·6 years (12·0-19·2) for HIV-2 infection (p<0·0001). Individuals who were infected with HIV-1 or HIV-2 before enrolment showed similar results. Comparison with uninfected individuals indicated limited confounding contribution from natural mortality. Mean CD4 percentages were higher in individuals with HIV-2 than in those with HIV-1 during early infection (28·0% [SE 1·3] vs 22·3% [1·7]; p=0·00094) and declined at a slower rate (0·4% [0·2] vs 0·9% [0·2] per year; p=0·028). HIV-2-infected individuals developed clinical AIDS at higher mean CD4 percentages (18·2%, IQR 7·2-25·4) than HIV-1-infected individuals (8·2%, 3·0-13·8; p<0·0001). INTERPRETATION: Our results show that both HIV-1-infected and HIV-2-infected individuals have a high probability of developing and dying from AIDS without antiretroviral treatment. FUNDING: Swedish International Development Agency, Swedish Research Council, Swedish Society of Medical Research, Medical Faculty at Lund University, and Region Skåne Research and Development.

CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection.

OBJECTIVE: HIV type 2 (HIV-2) represents an attenuated form of HIV, in which many infected individuals remain 'aviremic' without antiretroviral therapy. However, aviremic HIV-2 disease progression exists, and in the current study, we therefore aimed to examine if specific pathological characteristics of CD4 T cells are linked to such outcome. DESIGN: HIV-seronegative (n = 25), HIV type 1 (HIV-1) (n = 33), HIV-2 (n = 39, of whom 26 were aviremic), and HIV-1/2 dually (HIV-D) (n = 13)-infected study participants were enrolled from an occupational cohort in Guinea-Bissau. METHODS: CD4 T-cell differentiation, activation, exhaustion, senescence, and transcription factors were assessed by polychromatic flow cytometry. Multidimensional clustering bioinformatic tools were used to identify CD4 T-cell subpopulations linked to infection type and disease stage. RESULTS: HIV-2-infected individuals had early and late-differentiated CD4 T-cell clusters with lower activation (CD38HLA-DR) and exhaustion programmed death-1 (PD-1) than HIV-1 and HIV-D-infected individuals. We also noted that aviremic HIV-2-infected individuals possessed fewer individuals. CD4 T cells with pathological signs compared to other HIV-infected groups. Still, compared to HIV-seronegative individuals, aviremic HIV-2-infected individuals had T-bet CD4 T cells that showed elevated immune activation/exhaustion, and particularly the frequencies of PD-1 cells were associated with a suboptimal percentage of CD4 T cells. CONCLUSION: Increased frequencies of CD4 T cells with an activated/exhausted phenotype correlate with exacerbated immunodeficiency in aviremic HIV-2-infected individuals. Thus, these findings encourage studies on the introduction of antiretroviral therapy also to individuals with aviremic HIV-2 infection.

Elevated levels of invariant natural killer T-cell and natural killer cell activation correlate with disease progression in HIV-1 and HIV-2 infections.

OBJECTIVE: In this study, we aimed to investigate the frequency and activation of invariant natural killer T (iNKT) cells and natural killer (NK) cells among HIV-1, HIV-2, or dually HIV-1/HIV-2 (HIV-D)-infected individuals, in relation to markers of disease progression. DESIGN: Whole blood samples were collected from treatment-naive HIV-1 (n = 23), HIV-2 (n = 34), and HIV-D (n = 11) infected individuals, as well as HIV-seronegative controls (n = 25), belonging to an occupational cohort in Guinea-Bissau. METHODS: Frequencies and activation levels of iNKT and NK cell subsets were analysed using multicolour flow cytometry, and results were related to HIV-status, CD4 T-cell levels, viral load, and T-cell activation. RESULTS: HIV-1, HIV-D, and viremic HIV-2 individuals had lower numbers of CD4 iNKT cells in circulation compared with seronegative controls. Numbers of CD56 NK cells were also reduced in HIV-infected individuals as compared with control study participants. Notably, iNKT cell and NK cell activation levels, assessed by CD38 expression, were increased in HIV-1 and HIV-2 single, as well as dual, infections. HIV-2 viremia was associated with elevated activation levels in CD4 iNKT cells, CD56, and CD56 NK cells, as compared with aviremic HIV-2 infection. Additionally, disease markers such as CD4 T-cell percentages, viral load, and CD4 T-cell activation were associated with CD38 expression levels of both iNKT and NK cells, which activation levels also correlated with each other. CONCLUSION: Our data indicate that elevated levels of iNKT-cell and NK-cell activation are associated with viremia and disease progression markers in both HIV-1 and HIV-2 infections.

Cocirculation of several similar but unique HIV-1 recombinant forms in Guinea-Bissau revealed by near full-length genomic sequencing.

The dynamic HIV-1 epidemic has resulted in the emergence of several different subtypes and recombinant forms that may differ in biological properties. A recombinant form of CRF02_AG and subsubtype A3 (A3/02) was recently described based on env sequencing and was associated with faster disease progression rates compared with its parental strains. Here, we performed near full-length sequencing of the A3/02 variant to characterize the recombination patterns of a potential novel and more pathogenic circulating recombinant form of HIV-1 in Guinea-Bissau. HIV-1 proviral DNA was extracted from blood samples of individuals infected with the A3/02 recombinant form. The recombination patterns were investigated for six samples that were successfully amplified and sequenced. We found that all six full-length genomes were recombinant forms composed of CRF02_AG and A3 with a recombination hot-spot in the C2 region of env. However, the recombination patterns in the remaining genome differed between samples. Two samples displayed similar recombination profiles, indicative of a homogeneous recombinant form circulating in the population in Guinea-Bissau, whereas the remaining four samples represented unique recombinant forms. The characterization of five different recombination profiles indicated a high frequency of recombination. The recombination breakpoint in the C2 region was identified as the principal common feature shared between sequences, suggesting that this region may have an impact on disease progression rate. Since novel recombinant forms may have characteristics associated with a higher potential of spread in the human population, this study highlights the importance of continuous screening and surveillance of the HIV-1 epidemic.

Increased survival among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals.

OBJECTIVE: To compare survival times of HIV-1 single and HIV-1 and HIV-2 dual-infected individuals. DESIGN: Prospective open cohort study. METHODS: We analysed data from 259 HIV-1-seroincident cases (either HIV-1 single or HIV-1 and HIV-2 dual-infected) from a cohort with long follow-up (~20 years) in order to study the influence of type of infection and infection order on mortality. Sex and age at HIV-1 infection date was controlled for in a Cox proportional-hazards model. RESULTS: Dual-infected individuals had a 42% longer time from HIV-1 infection to death compared with single-infected individuals, adjusting for age asymmetries between groups. Dual-infected individuals with an HIV-2 infection preceding the HIV-1 infection had a more than two-fold lower mortality risk during follow-up than HIV-1 single-infected individuals. CONCLUSION: Survival time is longer and the risk of progression to death is lower among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals. This natural inhibition could have implications for the development of future HIV-1 vaccines and therapeutics.

Faster progression to AIDS and AIDS-related death among seroincident individuals infected with recombinant HIV-1 A3/CRF02_AG compared with sub-subtype A3.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) is divided into subtypes and circulating recombinant forms (CRFs) but the impact of subtype/CRF on disease progression is not fully understood. METHODS: We determined the HIV-1 subtype/CRF of 152 seroincident individuals from Guinea-Bissau, based on the C2-V3 region of env. Disease progression was measured as time from estimated seroconversion to AIDS and AIDS-related death. Hazard ratios (HRs) were calculated using a Cox proportional hazard model, adjusting for gender and age at seroconversion. RESULTS: The major subtypes/CRFs identified were CRF02_AG (53%), A3 (29%), and A3/02 (a recombinant of A3 and CRF02_AG) (13%). Infection with A3/02 was associated with a close to 3-fold increased risk of AIDS and AIDS-related death compared to A3 (HR = 2.6 [P = 0.011] and 2.9 [P = 0.032], respectively). The estimated time from seroconversion to AIDS and AIDS-related death was 5.0 and 8.0 years for A3/02, 6.2 and 9.0 years for CRF02_AG, and 7.2 and 11.3 years for A3. CONCLUSION: Our results show that there are differences in disease progression between HIV-1 A-like subtypes/CRFs. Individuals infected with A3/02 have among the fastest progression rates to AIDS reported to date. Determining the HIV-1 subtype of infected individuals could be important in the management of HIV-1 infections.

Declining prevalence rates of syphilis among police officers in Guinea-Bissau, West Africa, 1990-2010.

We analyzed prevalence rates of syphilis (positive Treponema pallidum hemagglutinin antigen/T. pallidum particle antigen and venereal disease research laboratory test) among police officers in Guinea-Bissau from 1990 to 2010 and found a significant decline from 4.5% to 0.4% (P = 0.0065). Our results are in line with other recent reports from West Africa. More research is needed to identify the reasons for this decline.

Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection.

BACKGROUND: Progressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood. METHODS: We analyzed data from 223 participants who were infected with HIV-1 after enrollment (with either HIV-1 infection alone or HIV-1 and HIV-2 infection) in a cohort with a long follow-up duration (approximately 20 years), according to whether HIV-2 infection occurred first, the time to the development of AIDS (time to AIDS), CD4+ and CD8+ T-cell counts, and measures of viral evolution. RESULTS: The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P=0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection. CONCLUSIONS: Our results suggest that HIV-1 disease progression is inhibited by concomitant HIV-2 infection and that dual infection is associated with slower disease progression. The slower rate of disease progression was most evident in participants with dual infection in whom HIV-2 infection preceded HIV-1 infection. These findings could have implications for the development of HIV-1 vaccines and therapeutics. (Funded by the Swedish International Development Cooperation Agency-Swedish Agency for Research Cooperation with Developing Countries and others.).

High sexual risk taking and diverging trends of HIV-1 and HIV-2 in the military of Guinea Bissau.

BACKGROUND: HIV and other sexually transmitted infections are a growing problem in the military personnel of Africa, and information about this problem in Guinea-Bissau is lacking. The aims of this study were to determine the prevalence and trends of the HIV epidemics in the military forces of Guinea Bissau and to explore possible risk factors for HIV infection. METHODOLOGY: Repeated cross-sectional surveys of HIV-1 and HIV-2 were conducted between 1992 and 2005, and knowledge, sexual behaviour and risk factors for HIV-1 and HIV-2 in military personnel in Guinea-Bissau were assessed. RESULTS: The seroprevalence of HIV-1, HIV-2 and HIV-1+HIV-2 dual reactivity was 1.1%, 8.4% and 0.1% in 1992-95, and in 2005 7.7%, 5.1% and 1.9%, respectively. Both the increase of HIV-1 and the decline of HIV-2 between 1992-95 and 2005 were significant when adjusted for age (p < 0.001 for both changes). Only a minority did not know how HIV transmits, but sexual risk taking was high. Several significant risk factors were found in univariate analyses for HIV-1 and HIV-2, but the only risk factor that remained significant after multivariate regression analysis was previous contact with a prostitute among HIV-1-positive subjects (single and dually reactive) (p < 0.01). CONCLUSION: The increasing trend of HIV-1 and the high risky sexual behavior illustrate the need for improvement in HIV/AIDS prevention efforts among military personnel in Guinea Bissau.

Human exposure to persistent organic pollutants in West Africa--a temporal trend study from Guinea-Bissau.

BACKGROUND: Humans, independent on where they live, are exposed to complex and various mixtures of chemicals, including persistent organic pollutants (POPs). The variability of the exposure depends on sources of the chemicals and is influenced by e.g. geography, social and cultural heritage. While exposures to POPs are frequently studied in populations from developed industrial countries, very little is known on levels and trends of POPs in developing countries, especially in Africa. OBJECTIVES: The aim of the present study was to investigate levels and temporal trends of POPs in adults from Guinea-Bissau. METHODS: Serum samples were obtained from an open cohort of police officers in Guinea-Bissau. Repeated samples from 33 individuals were obtained at five time points between 1990 and 2007, in all 147 samples. Pooled serum samples were extracted and cleaned-up prior to analysis by gas chromatography and mass spectrometry. The concentration of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (4,4'-DDT) and its metabolites, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and hexachlorocyclohexanes (HCHs) were determined. RESULTS: The major POP found in all samples was 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (4,4'-DDE) followed by 4,4'-DDT. 4,4'-DDE, 4,4'-DDT, PCBs and beta- and gamma-HCH were significantly decreasing over time. The PBDEs were found at low concentrations, with an increasing temporal trend for BDE-153. CONCLUSION: National and international management may be behind the observed decreased organohalogen compound concentrations in humans from Guinea-Bissau from the early 1990's and onwards, similarly to the development of these compounds in humans from industrial countries. In contrast, PBDEs follow a trend of increasing concentrations even though at low levels.

Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections.

Microbial translocation has been linked to systemic immune activation during human immunodeficiency virus (HIV) type 1 infection. Here, we show that an elevated level of microbial translocation, measured as plasma lipopolysaccharide (LPS) concentration, correlates with AIDS in both individuals infected with HIV type 1 and individuals infected with HIV type 2. LPS concentration also correlates with CD4+ T cell count and viral load independently of HIV type. Furthermore, elevated plasma LPS concentration was found to be concomitant with defective innate and mitogen responsiveness. We suggest that microbial translocation may contribute to loss of CD4+ T cells, increase in viral load, and defective immune stimuli responsiveness during both HIV type 1 and HIV type 2 infections.

Frequent CXCR4 tropism of HIV-1 subtype A and CRF02_AG during late-stage disease--indication of an evolving epidemic in West Africa.

BACKGROUND: HIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease. RESULTS: We found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%). CONCLUSIONS: The increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.

Prevalence and incidence of HIV-1 and HIV-2 before, during and after a civil war in an occupational cohort in Guinea-Bissau, West Africa.

OBJECTIVES: To study prevalence and incidence of HIV-1 and HIV-2 between 1990 and 2007 and to examine impact of the civil war in 1998-1999. We also wanted to investigate possible interaction between HIV-1 and HIV-2. DESIGN: Open prospective cohort study of 4592 police officers in Guinea-Bissau, West Africa. METHODS: Analysis of HIV-1 and HIV-2 prevalence and incidence divided in 2-3 years time strata. RESULTS: HIV-1 prevalence (including HIV-1/HIV-2 dual reactivity) increased gradually from 0.6 to 3.6% before the war and was 9.5% in the first serosurvey after the war. HIV-1 incidence more than doubled during and shortly after the war, from 0.50 to 1.22 per 100 person-years. Both prevalence and incidence of HIV-1 decreased in the following periods after the war. HIV-2 prevalence decreased from 13.4 to 6.2% during the entire study period and HIV-2 incidence decreased from 1.38 to 0.18 per 100 person-years. Adjusted incidence rate ratios of HIV-1 incidence in HIV-2-positive participants compared with HIV-negative participants ranged from 1.02 to 1.18 (not significant) depending on the confounding variables included. CONCLUSION: HIV-1 has increased, whereas HIV-2 has decreased and the risk of acquiring HIV-1 is now more than four times higher as compared with HIV-2. The civil war in 1998-1999 appears to have induced a temporary increase in HIV-1 transmission, but now a stabilization of HIV-1 incidence and prevalence seems to have taken place. There was no evidence of a protective effect of HIV-2 against HIV-1 infection.