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Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.

ABSTRACT: Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele.

SUBMITTER: Chopera DR

PROVIDER: S-EPMC3126593 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.

Chopera D R DR Mlotshwa M M Woodman Z Z Mlisana K K de Assis Rosa D D Martin D P DP Abdool Karim S S Gray C M CM Williamson C C

Journal of virology 20110525 14

Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could ex ...[more]

PMID: 21613398

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Project description:BackgroundThe challenges of identifying acute HIV infection (AHI) have resulted in a lack of critical information on early AHI that constrains the development of therapeutics that are designed to eradicate HIV from the infected host.MethodsAHI participants were recruited from the Thai Red Cross Anonymous Clinic in Bangkok, Thailand into the RV254/SEARCH010 protocol and categorised according to Fiebig stages as follows: Fiebig I (HIV-RNA+, p24 Ag-, HIV IgM-) and Fiebig II-IV (HIV-RNA+, p24 Ag + or -, HIV IgM- or +, Western blot- or indeterminate). Proviral and viral burden and immune activation levels were compared between Fiebig stage groups at the time of AHI. CD4 and CD4/CD8 ratio were also compared between groups before and up to 96 weeks of ART.ResultsMedian age was 27 years and 96% were male. Fiebig I individuals had lower median HIV-DNA in mononuclear cells from blood (3 vs. 190 copies/106 cells) and gut (0 vs. 898 copies/106 cells), and lower HIV-RNA in blood (4.2 vs. 6.2 log10 copies/mL), gut (1.7 vs. 3.1 log10 copies/mg) and cerebrospinal fluid (2.0 vs. 3.8 log10 copies/mL), when compared to Fiebig II-IV individuals (all P<0.01). Median plasma sCD14 level was lower (1.1 vs. 1.6 μg/mL) in Fiebig I individuals as was the frequency of CD8+HLADR+CD38+ T cells in blood (7.6 vs. 14.9%, both P<0.05). The median plasma interleukin 6 levels were similar between stages (0.6 in Fiebig I vs. 0.5 pg/mL in Fiebig II-IV, P>0.05). The frequencies of CD4+HLA-DR+CD38+ T cells were also similar between these stages (2.1 vs. 2.6%, P>0.05). Median CD4 count and CD4/CD8 ratio were higher in Fiebig I: 508 vs. 340 cells/mm3 and 1.1 vs. 0.7, respectively (both P<0.001). After ART, CD4 cell count normalised by week 24 in Fiebig I and week 48 in Fiebig II-IV. However, CD4/CD8 ratio was lower in both groups after 96 weeks of ART compared to healthy Thais (P=0.02).ConclusionsCompared to later AHI stages, Fiebig I was associated with lower HIV burden in blood and tissue compartments, lower immune activation and higher CD4 and CD4/CD8 ratio. ART in Fiebig I-IV resulted in normalisation of CD4 cell count within the first year, supporting the benefit of early ART. However, the CD4/CD8 ratio was not normalised after 2 years of ART in all AHI stages, suggesting some degree of persistent immunological dysfunction even when ART was instituted as early as Fiebig I.

Project description:BACKGROUND:The aim of the present study was to evaluate patient factors that affect the progression of anal dysplasia in human immunodeficiency virus (HIV)-positive individuals. METHODS:A retrospective cohort study of HIV-positive adults with human papilloma virus related anal lesions was performed from 2012 to 2017. All patients underwent surgical excision or biopsy and fulguration of lesions in the operating room without using high resolution anoscopy. Patients with initial presentation of squamous cell carcinoma were excluded. The study was designed to investigate progression between the first available histology and either the follow up histology or a negative examination. Patient files were reviewed and data was collected. A bivariate analysis of continuous and categorical variables was performed. RESULTS:One hundred and sixty-one patients met the inclusion criteria. Ninety-seven percent were male. Mean age was 41 years. Thirty-five percent were African American and 47% were Caucasian. After a median follow-up interval of 331 days (IQR 120-615 days) 14 (9%) of patients had progression of disease. Visible lesions on initial presentation, as opposed to lesions found in patients undergoing examination under anesthesia because of HSIL on anal pap smear, was associated with progression (p = 0.0.2). A lower initial CD4 count (p?=?0.01) and initial surgical pathology of anal condylomata (p?=?0.01) were also associated with progression. High-risk serotype was associated with no change or regression (p?=?0.01). CONCLUSIONS:In our large cohort of HIV-positive patients treated without high resolution anoscopy the rate of progression was low. Most notably, visible lesions at initial presentation and CD4 count when lower were associated with progression. Initial surgical pathology of anal condylomata was associated with progression, while high-risk serotypes correlated with regression or stability. Identification of risk factors has important implications concerning postoperative surveillance and counseling of HIV-positive patients with anal condylomata/ anal dysplasia.

Dataset Information

Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.

Publications

Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.

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