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Host and viral genetic correlates of clinical definitions of HIV-1 disease progression.

ABSTRACT: BACKGROUND: Various patterns of HIV-1 disease progression are described in clinical practice and in research. There is a need to assess the specificity of commonly used definitions of long term non-progressor (LTNP) elite controllers (LTNP-EC), viremic controllers (LTNP-VC), and viremic non controllers (LTNP-NC), as well as of chronic progressors (P) and rapid progressors (RP). METHODOLOGY AND PRINCIPAL FINDINGS: We re-evaluated the HIV-1 clinical definitions, summarized in Table 1, using the information provided by a selected number of host genetic markers and viral factors. There is a continuous decrease of protective factors and an accumulation of risk factors from LTNP-EC to RP. Statistical differences in frequency of protective HLA-B alleles (p-0.01), HLA-C rs9264942 (p-0.06), and protective CCR5/CCR2 haplotypes (p-0.02) across groups, and the presence of viruses with an ancestral genotype in the "viral dating" (i.e., nucleotide sequences with low viral divergence from the most recent common ancestor) support the differences among principal clinical groups of HIV-1 infected individuals. CONCLUSIONS: A combination of host genetic and viral factors supports current clinical definitions that discriminate among patterns of HIV-1 progression. The study also emphasizes the need to apply a standardized and accepted set of clinical definitions for the purpose of disease stratification and research.

SUBMITTER: Casado C

PROVIDER: S-EPMC2884031 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Host and viral genetic correlates of clinical definitions of HIV-1 disease progression.

Casado Concepción C Colombo Sara S Rauch Andri A Martínez Raquel R Günthard Huldrych F HF Garcia Soledad S Rodríguez Carmen C Del Romero Jorge J Telenti Amalio A López-Galíndez Cecilio C

PloS one 20100611 6

<h4>Background</h4>Various patterns of HIV-1 disease progression are described in clinical practice and in research. There is a need to assess the specificity of commonly used definitions of long term non-progressor (LTNP) elite controllers (LTNP-EC), viremic controllers (LTNP-VC), and viremic non controllers (LTNP-NC), as well as of chronic progressors (P) and rapid progressors (RP).<h4>Methodology and principal findings</h4>We re-evaluated the HIV-1 clinical definitions, summarized in Table 1, ...[more]

PMID: 20552027

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Project description:BackgroundVariants in HIV-coreceptor C-C chemokine receptor type 5 (CCR5) and Human leukocyte antigen (HLA) genes are the most important host genetic factors associated with HIV infection and disease progression. Our aim was to analyze the association of these genetic factors in the presence of clinical symptoms during Primary HIV Infection (PHI) and disease progression within the first year.MethodsSeventy subjects diagnosed during PHI were studied (55 symptomatic and 15 asymptomatic). Viral load (VL) and CD4 T-cell count were evaluated. HIV progression was defined by presence of B or C events and/or CD4 T-cell counts <350 cell/mm3. CCR5 haplotypes were characterized by polymerase chain reaction and SDM-PCR-RFLP. HLA-I characterization was performed by Sequencing.ResultsSymptoms during PHI were significantly associated with lower frequency of CCR5-CF1 (1.8% vs. 26.7%, p = 0.006). Rapid progression was significantly associated with higher frequency of CCR5-CF2 (16.7% vs. 0%, p = 0.024) and HLA-A*11 (16.7% vs. 1.2%, p = 0.003) and lower frequency of HLA-C*3 (2.8% vs. 17.5%, p = 0.035). Higher baseline VL was significantly associated with presence of HLA-A*11, HLA-A*24, and absence of HLA-A*31 and HLA-B*57. Higher 6-month VL was significantly associated with presence of CCR5-HHE, HLA-A*24, HLA-B*53, and absence of HLA-A*31 and CCR5-CF1. Lower baseline CD4 T-cell count was significantly associated with presence of HLA-A*24/*33, HLA-B*53, CCR5-CF2 and absence of HLA-A*01/*23 and CCR5-HHA. Lower 6-month CD4 T-cell count was associated with presence of HLA-A*24 and HLA-B*53, and absence of HLA-A*01 and HLA-B*07/*39. Moreover, lower 12-month CD4 T-cell count was significantly associated with presence of HLA-A*33, HLA-B*14, HLA-C*08, CCR5-CF2, and absence of HLA-B*07 and HLA-C*07.ConclusionSeveral host factors were significantly associated with disease progression in PHI subjects. Most results agree with previous studies performed in other groups. However, some genetic factor associations are being described for the first time, highlighting the importance of genetic studies at a local level.

Project description:Genetic and immunologic analyses of epidemiologically-linked HIV transmission enable insights into the impact of immune responses on clinical outcomes. Human vaccine trials and animal studies of HIV-1 infection have suggested immune correlates of protection; however, their role in natural infection in terms of protection from disease progression is mostly unknown. Four HIV-1+ Cameroonian individuals, three of them epidemiologically-linked in a polygamous heterosexual relationship and one incidence-matched case, were studied over 15 years for heterologous and cross-neutralizing antibody responses, antibody binding, IgA/IgG levels, antibody-dependent cellular cytotoxicity (ADCC) against cells expressing wild-type or CD4-bound Env, viral evolution, Env epitopes, and host factors including HLA-I alleles. Despite viral infection with related strains, the members of the transmission cluster experienced contrasting clinical outcomes including cases of rapid progression and long-term non-progression in the absence of strongly protective HLA-I or CCR5Δ32 alleles. Slower progression and higher CD4/CD8 ratios were associated with enhanced IgG antibody binding to native Env and stronger V1V2 antibody binding responses in the presence of viruses with residue K169 in V2. ADCC against cells expressing Env in the CD4-bound conformation in combination with low Env-specific IgA/IgG ratios correlated with better clinical outcome. This data set highlights for the first time that V1V2-directed antibody responses and ADCC against cells expressing open, CD4-exposed Env, in the presence of low plasma IgA/IgG ratios, can correlate with clinical outcome in natural infection. These parameters are comparable to the major correlates of protection, identified post-hoc in the RV144 vaccine trial; thus, they may also modulate the rate of clinical progression once infected. The findings illustrate the potential of immune correlate analysis in natural infection to guide vaccine development.

Project description:The course of Human Immunodeficiency Virus type 1 (HIV) infection is a dynamic interplay in which both host and viral genetic variation, among other factors, influence disease susceptibility and rate of progression. HIV set-point viral load (spVL), a key indicator of HIV disease progression, has an estimated 30% of variance attributable to common heritable effects and roughly 70% attributable to environmental factors and/or additional non-genetic factors. Genome-wide genotyping and sequencing studies have allowed for large-scale association testing studying host and viral genetic variants associated with infection and disease progression. Host genomics of HIV infection has been studied predominantly in Caucasian populations consistently identifying human leukocyte antigen (HLA) genes and C-C motif chemokine receptor 5 as key factors of HIV susceptibility and progression. However, these studies don't fully assess all classes of genetic variation (e.g., very rare polymorphisms, copy number variants etc.) and do not inform on non-European ancestry groups. Additionally, viral sequence variability has been demonstrated to influence disease progression independently of host genetic variation. Viral sequence variation can be attributed to the rapid evolution of the virus within the host due to the selective pressure of the host immune response. As the host immune system responds to the virus, e.g., through recognition of HIV antigens, the virus is able to mitigate this response by evolving HLA-specific escape mutations. Diversity of viral genotypes has also been correlated with moderate to strong effects on CD4+ T cell decline and some studies showing weak to no correlation with spVL. There is evidence to support these viral genetic factors being heritable between individuals and the evolution of these factors having important consequences in the genetic epidemiology of HIV infection on a population level. This review will discuss the host-pathogen interaction of HIV infection, explore the importance of host and viral genetics for a better understanding of pathogenesis and identify opportunities for additional genetic studies.

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Host and viral genetic correlates of clinical definitions of HIV-1 disease progression.

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Host and viral genetic correlates of clinical definitions of HIV-1 disease progression.

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