Genomic architecture of HIV-1 infection: current status & challenges

Abstract

Studies on host genomics have revealed the existence of identifiable HIV-1 specific protective factors among infected individuals who remain naturally resistant viraemia controllers with little or no evidence of virus replication. These factors are broadly grouped into those that are immune associated (MHC, chemokines, cytokines, CTLs and others), linked to viral entry (chemokine co-receptors and ligands), act as post-entry restriction elements (TRIM5a, APOBEC3) and those associated with viral replication (cytokines and others). These features have been identified through multiple experimental approaches ranging from candidate gene approaches, genome wide association studies (GWAS), expression analysis in conjunction with functional assays in humans to primate based models. Several studies have highlighted the individual and population level gross differences both in the viral clade sequences as well as host determined genetic associations. This review collates current information on studies involving major histocompatibility complex (MHC) as well as non MHC genes in the context of HIV-1 infection and AIDS involving varied ethnic groups. Special focus of the review is on the genetic studies carried out on the Indian population. Further challenges with regard to therapeutic interventions based on current knowledge have been discussed along with discussion on documented cases of stem cell therapy and very early highly active antiretroviral therapy (HAART) interventions.

Fig. 1

‘HIV clock’ showing major landmarks in research and therapy relating HIV/AIDS pandemic since its inception apparently in early 1980s’. ART, antiretroviral therapy; HSCT, hematopoietic stem cell transplantation; GWAS, genome-wide association studies; HPV, human papilloma virus.

Fig. 2

Association of three HLA-B alleles viz. HLA-B27, B57 and B35 with susceptibility to HIV-1/AIDS. The alleles B27 and B57 are protective while B35Px alleles are disease predisposing. It is possible that the protective nature of B27 and B57 may decline in time since the virus is continually trying to evolve escape mutants and change its immune landscape depending upon the HLA signatures of the host. The HLA system which is the human MHC, contains polymorphic class I (HLA-A, B, C), class II (HLA-DR, DQ and DP) and a set of central genes that include complement, tumour necrosis factor (TNF), MHC class 1 polypeptide-related sequence A (MICA) and other genes (For details of the MHC gene products in man please see Ref. 12).

Fig. 3

Gene map of the human MHC on chromosome 6p21.3 showing various single nucleotide polymorphisms (SNPs) identified in the HLA class I region that are associated with HIV-1/AIDS through genome wide association studies (GWAS) studies. Multiple gene loci are implicated in HIV-1 susceptibility and viraemia control.

Fig. 4

A comparison of frequencies of genetic polymorphisms in CCR5 chemokine ligands (RANTES, MIP1a), CCR2 ligand (MCP1) and CXCR4 ligand (SDF-1) among the healthy north Indian population and HIV-1 infected individuals. The three significant findings in MIP1α associations and their odds ratios respectively are shown inside an insert on right lower side panel of the figure (Source: unpublished data). *P<0.05; Healthy vs HIV-1 seropositive individuals.

Fig. 5

A correlation of prevalence of TIM1 haplotypes and CD4 T cell counts in the north Indian population. The panel (a) shows % frequencies of TIM1 haplotypes among healthy and HIV-1 seropositive individuals. Panel (b) shows higher CD4T counts among individuals carrying D3A haplotypes among patients. Panel (c) shows two possible outcomes of lower levels of TIM1 expression among individuals carrying D3A, one favouring HIV-1 replication and the other favouring slower progression.