Sehu Sabally

HIV-2-infected patients survive longer than HIV-1-infected patients

ObjectiveTo compare survival of patients infected with HIV-1 and HIV-2. DesignLongitudinal follow-up of 175 HIV-1-and 294 HIV-2-infected patients identified in, or referred to a hospital in The Gambia. MethodsSurvival analysis methods were used and the death rate ratios for HIV-2 relative to HIV-1 patients were estimated using proportional hazard regression models that allowed for age, sex and clinical or immunological features. ResultsThe overall death rate ratio for HIV-2 relative to HIV-1 was 0.67 [95% confidence interval (Cl), 0.49–0.91] when adjusted for age, sex and World Health Organization Bangui clinical classification. When allowing for age, sex and three strata of CD4+ count, the rate ratio was 0.64 (95% Cl, 0.43–0.94), and for three strata of β2-microglobulin levels 0.60 (95% Cl, 0.42–0.84). ConclusionMortality rate in HIV-2-infected patients is approximately two-thirds of that for HIV-1-infected patients.

Broadly cross-reactive HIV-specific cytotoxic T-lymphocytes in highly-exposed persistently seronegative donors.

HIV-specific cytotoxic T-lymphocytes (CTL) are believed to play a key part in the control of virus levels throughout HIV infection. An important goal of a potential prophylactic vaccine against HIV is therefore to elicit a strong CTL response which is broadly cross-reactive against a diverse range of HIV strains. We have detected HIV-specific CTL in two groups of highly-exposed but persistently seronegative female sex workers in Africa which show extensive cross-reactivity between different viral sequences. In a small group of women exposed to both HIV-1 and HIV-2 in Gambia, studied over 4 years, we have repeatedly detected HLA-B35-restricted CTL which exhibit cross-reactivity between the HIV-1 and HIV-2 sequences of the CTL epitopes. In women with particularly intense exposure to what are likely to be multiple clades of HIV-1 in Nairobi Kenya, we have detected CTL directed towards epitopes conserved between HIV-1 clades. In neither group is there any evidence that variation in CCR5 sequence or expression is responsible for their apparent resistance to HIV infection. However, in seropositive donors from Oxford infected with African strains of HIV-1, we have defined CTL responses which are specific for particular clades and have mapped some unique A clade CTL epitopes, together with others to highly-conserved regions of the virus. Further information about the extent of cross-reactive CTL immunity will be important for future vaccine design and evaluation.

Absence of specific mucosal antibody responses in HIV-exposed uninfected sex workers from the Gambia

ObjectivesSpecific antibodies to HIV envelope that inactivate virus at the mucosal surfaces involved in sexual contact are of interest for the design of a vaccine against HIV-1. It has been suggested that, in frequently HIV-exposed but uninfected individuals, HIV-specific mucosal antibody responses may exist and play a role in resistance against HIV. This study investigated HIV-1 envelope specific mucosal antibody responses in HIV-resistant sex workers in west Africa. MethodsA group of 26 exposed uninfected female commercial sex workers from the Gambia, who have had repeated exposures to HIV-1 and HIV-2 were studied. We assessed the presence of vaginal IgA and IgG in vaginal swabs against a range of HIV-1 and HIV-2 envelope presentations and performed HIV-1 neutralization assays. ResultsNo significant vaginal IgA or IgG responses against HIV-1 or HIV-2 were detected, and none of the vaginal secretions tested displayed any HIV-1 neutralizing activity. ConclusionVaginal antibody responses against HIV were not found in Gambian sex workers who resist HIV infection. Resistance against HIV infection can therefore occur in the absence of specific antibodies against HIV at the genital mucosa. A protective role for HIV-envelope specific IgA in resistance against HIV-1 infection in exposed uninfected individuals as reported in the literature is uncertain.

Rate of decline of percentage CD4+ cells is faster in HIV-1 than in HIV-2 infection

Increasing evidence suggests that the pathogenesis of HIV-1 is different from that of HIV-2. Thus, we have measured, longitudinally at various times over a median follow-up of 2.1 years, the percentage CD4+ cells of 94 patients infected with HIV-1 and 164 patients infected with HIV-2. The pattern of decline of CD4% over time was linear for patients with either infection. Multilevel statistical modeling techniques showed that after stratifying for HIV status, the rate of decline of CD4% was faster among patients who died than among those who survived (difference in rate of decline = 2.34% CD4+ cells/year; p = 0.0002). After stratifying for survival status, the rate of decline was faster and less variable among patients infected with HIV-1 than among patients infected with HIV-2 (difference in rate of decline = 1.12% CD4+ cells/year; p = 0.05). The proportion of patients who showed no fall in CD4+ cells was higher in HIV-2 than in HIV-1 infection (p = 0.026). These data suggest fundamental differences between the two infections, with HIV-1 being more pathogenic resulting in a faster and more homogeneous rate of decline than HIV-2. In HIV-2 infection, disease in many patients progresses slowly, but in some the advance is just as fast as that in HIV-1 infection. The reasons for this marked heterogeneity need elucidation to understand the disease and to target therapeutic interventions against HIV-2 in those most at risk.

Plasma RNA viral load predicts the rate of CD4 T cell decline and death in HIV-2-infected patients in West Africa.

ObjectiveTo examine whether the levels of plasma RNA and DNA provirus predict the rate of CD4 cell decline and patient death. DesignRetrospective analysis of HIV-2 cohort subjects. MethodsFifty-two subjects were recruited between January 1991 and December 1992. HIV-2 RNA levels in plasma and DNA levels in peripheral blood mononuclear cells (PBMC) were measured using in-house quantitative PCR assays. The annual rate of CD4 cell decline was calculated using the least-squares method. The survival data on 31 December 1997 were used. ResultsThe mean percentage of CD4 cells at baseline was 30.7 (SD, 9.5). In a linear regression model, the annual rate of CD4 cell decline was 1.76 CD4% faster for every increase in one log10 RNA copies/ml [95% confidence interval (CI), 0.81–2.7;P = 0.0006;r = 0.46; n = 52] and 1.76 CD4% faster for every increase in log10 DNA copies/105 PBMC (95% CI 0.46–3.1;P = 0.01;r = 0.33; n = 42). In a multiple linear regression model, RNA load was related to CD4 decline independently of DNA load (P = 0.02). The overall mortality rate was 7.29/100 person-years. In a Cox regression model, the hazard rate increased by 2.12 for each log10 increase in RNA load (95% CI, 1.3–3.5;P = 0.0023) but only by 1.09 for each log10 increase in DNA load (95% CI, 0.64–1.87;P = 0.8). ConclusionThis longitudinal study shows for the first time that a baseline HIV-2 RNA load predicts the rate of disease progression. HIV-2-infected patients with a high viral load may need to be treated as vigorously as HIV-1 patients.

Cytotoxic T lymphocytes recognize structurally diverse, clade‐specific and cross‐reactive peptides in human immunodeficiency virus type‐1 gag through HLA‐B53

Human immunodeficiency virus type‐1 (HIV‐1) cytotoxic T lymphocyte (CTL) epitopes have largely been defined in Caucasian populations infected with clade B virus. Identification of potentially protective CTL epitopes in non‐B clade‐infected African subjects is important for vaccine development. In a study of CTL responses in clade A‐infected Gambians, using cytotoxicity, interferon‐γ (IFN‐γ) enzyme‐linked immunospot (ELISpot) and HLA‐B53‐peptide tetramer assays, we identified three HLA‐B53‐restricted epitopes in HIV‐1 gag p24. CTL specific for an epitope in a highly immunogenic region of the p24 protein showed no cross‐reactivity to other HIV‐1 clades. Two of the epitopes would not have been predicted from the peptide‐binding motif due to the absence of a proline anchor at position 2. Structural analysis of HLA‐B53 and its relative, HLA B35, enabled us to re‐define the peptide‐binding motif to include other P2 anchors. These results demonstrate the value of combined immunological and structural analyses in defining novel CTL epitopes and have implications for HIV‐1 vaccine design.

Greater CD8+ TCR Heterogeneity and Functional Flexibility in HIV-2 Compared to HIV-1 Infection

Virus-specific CD8+ T cells are known to play an important role in the control of HIV infection. In this study we investigated whether there may be qualitative differences in the CD8+ T cell response in HIV-1- and HIV-2-infected individuals that contribute to the relatively efficient control of the latter infection. A molecular comparison of global TCR heterogeneity showed a more oligoclonal pattern of CD8 cells in HIV-1- than HIV-2-infected patients. This was reflected in restricted and conserved TCR usage by CD8+ T cells recognizing individual HLA-A2- and HLA-B57-restricted viral epitopes in HIV-1, with limited plasticity in their response to amino acid substitutions within these epitopes. The more diverse TCR usage observed for HIV-2-specific CD8+ T cells was associated with an enhanced potential for CD8 expansion and IFN-γ production on cross-recognition of variant epitopes. Our data suggest a mechanism that could account for any possible cross-protection that may be mediated by HIV-2-specific CD8+ T cells against HIV-1 infection. Furthermore, they have implications for HIV vaccine development, demonstrating an association between a polyclonal, virus-specific CD8+ T cell response and an enhanced capacity to tolerate substitutions within T cell epitopes.

CD8+ T cell responses to human immunodeficiency viruses type 2 (HIV-2) and type 1 (HIV-1) gag proteins are distinguishable by magnitude and breadth but not cellular phenotype.

The mechanisms underlying the relatively slow progression of human immunodeficiency virus type 2 (HIV‐2) compared with HIV‐1 infection are undefined and could be a result of more effective immune responses. We used HIV‐2 and HIV‐1 IFN‐γ enzyme‐linked immunospot assays to evaluate CD8+ T cell responses in antiretroviral‐naive HIV‐2‐ (‘HIV‐2+’) and HIV‐1‐infected (‘HIV‐1+’) individuals. Gag‐specific responses were detected in the majority of HIV‐2+ and HIV‐1+ subjects. Overlapping gag peptide analysis indicated a significantly greater magnitude and breadth of responses in the HIV‐1+ cohort, and this difference was attributable to low responses in HIV‐2+ subjects with undetectable viral load (medians 2107 and 512 spot‐forming units per 106 PBMC, respectively, p=0.007). We investigated the phenotype of viral epitope‐specific CD8+ T cells identified with HLA‐B53‐ and HLA‐B58‐peptide tetramers (8 HIV‐2+, 11 HIV‐1+ subjects). HIV‐2‐specific CD8+ T cells were predominantly CD27+ CD45RA–, and only a minority expressed perforin. The limited breadth and low frequency of CD8+ T cell responses to HIV‐2 gag in aviremic HIV‐2+ subjects suggests that these responses reflect antigen load in plasma, as is the case in HIV‐1 infection. Immune control of HIV‐2 does not appear to be related to the frequency of perforin‐expressing virus‐specific CD8+ T cells.

Immunological responses of Gambians in relation to clinical stage of HIV-2 disease

This study describes a broad spectrum of cellular and antibody‐mediated immune responses found in 28 asymptomatic and 37 symptomatic Gambian patients with HIV‐2 infection. It shows that these responses vary according to the stage of infection as described by three clinical staging systems. The first system was a local one based on the signs used for the WHO Bangui clinical definition of AIDS, the second, suggested by WHO, was based on a performance scale, and the third was that used by the Centre for Disease Control. Asymptomatic patients had significantly lower mean CD4 counts, lymphoproliferative and interferon‐gamma (IFN‐γ) responses and lower IgG and IgM antibody responses to keyhole limpet haemocyanin (KLH) than controls. These measurements and the size of the skin test reaction to purified protein derivative (PPD) or Candida antigen declined significantly according to the stage of infection. Mean values of the serological markers β2‐microglobulin and neopterin and antibody titres to Epstein‐Barr virus capsid antigen (EBVCA) rose significantly according to severity of disease. The Gambian or WHO clinical staging systems, which are easy and cheap to apply, may serve as an alternative to sophisticated and expensive immunological measurements when trying to stage disease and predict prognosis.

Proviral load and immune function in blood and lymph node during HIV-1 and HIV-2 infection.

Proviral load as well as lymphocyte phenotype and function were compared in peripheral blood and lymph node compartments of 17 HIV‐1, 12 HIV‐2 and three dually infected patients with lymphadenopathy. The mean percentage (95% confidence interval (CI)) of CD4+ cells was higher in lymph node mononuclear cells (LNMC) than in peripheral blood mononuclear cells (PBMC) in both infections, being 26.7% (21.1%, 32.3%) and 15.3% (10.4%, 20.2%), respectively, for HIV‐1‐infected patients (P = 0.0001) and 32.3% (22.7%, 41.9%) and 22.1% (13.6%, 30.6%), respectively, for HIV‐2‐infected patients (P = 0.02). In both types of infection, proviral load adjusted for number of CD4+ cells was higher in LNMC than in PBMC: the geometric mean (95% CI) was 8937 (4991; 16 003) and 4384 (2260; 8503), respectively, for HIV‐1 patients (P = 0.02) and 1624 (382; 6898) and 551 (147; 2058) DNA copies, respectively, for HIV‐2 patients (P = 0.05). Proviral load in both compartments was closely correlated (HIV‐1, r = 0.60, P = 0.01; and HIV‐2, r = 0.83, P = 0.0003). In both infections, proliferation and interferon‐gamma (IFN‐γ) production in response to purified protein derivative (PPD) was lower in LNMC than in PBMC, both of which, in turn, were lower than in healthy controls. These results indicate that in HIV‐2 as in HIV‐1 infection, infected cells have a tropism for the lymph nodes resulting in higher viral load in this compartment and lower lymphocyte responses to the recall antigen PPD which may increase susceptibility to tuberculosis.