Host genes associated with HIV/AIDS: advances in gene discovery

Abstract

Twenty-five years after the discovery of HIV as the cause of AIDS there is still no effective vaccine and no cure for this disease. HIV susceptibility shows a substantial degree of individual heterogeneity, much of which can be conferred by host genetic variation. In an effort to discover host factors required for HIV replication, identify crucial pathogenic pathways, and reveal the full armament of host defenses, there has been a shift from candidate-gene studies to unbiased genome-wide genetic and functional studies. However, the number of securely identified host factors involved in HIV disease remains small, explaining only approximately 15-20% of the observed heterogeneity - most of which is attributable to human lymphocyte antigen (HLA) variants. Multidisciplinary approaches integrating genetic epidemiology to systems biology will be required to fully understand virus-host interactions to effectively combat HIV/AIDS.

Figure 1

A typical natural course of HIV infection. (i) Individual infected with HIV-1; (ii) Acute phase lasting for 6-12 weeks with flu-like symptoms, peak viral load and drop in CD4+ T cells; (iii) Chronic asymptomatic phase last on average for 7-10 years; following the acute phase, viral replication reaches a steady level known as ‘set point’; (iv) AIDS onset is associated with increasing viral replication and declining CD4⁺ cells decline to < 200/mm³; time to the AIDS onset vary in individuals ranging from as little as 2 years to more than 15 years after seroconversion. The figure was modified from Ref[84].

Figure 2

Study groups and phenotypes in HIV-1 genetic association analysis. Case-control and cohort studies are used to evaluate genetic impact on HIV-1 infection or disease progression by assessing an AIDS-predicting phenotype (setpoint viral load), time from infection to a specific outcome (e.g. CD4⁺ cell, AIDS and Death), or case-control comparison between fast, median and non-progressors.

Figure 3. Host factors that interact with HIV

HIV-1 co-opts host cellular factors for its life cycle: cell entry, uncoating, reverse transcription to viral DNA, nucleus entry, integration into host DNA, transcription of viral RNA, assembling and budding of new virions. Cellular factors such as CCR5, CD4 and CypA promote and other factors such as TRIM5α and APOBEC3G impede HIV replication.

Figure 4. Replication among GWAS, silencing RNA screen, and candidate gene studies

Genes identified from a GWAS [71], gene silencing screens [75-78] and numerous candidate gene studies (Table 1) were compared for overlapping genes. ZNRD1 was identified in two of the siRNA screens [75, 78] and in the Fellay GWAS [71]. HCP5 tracks HLA-B*57, a well-defined, protective HLA allele. HLA-C was uniquely revealed by GWAS. This gene would not be identified by siRNA screens targeting intracellular factors. Genes from silencing RNA studies that were identified in two out of four studies are indicated [75-78, 85]. Genes in parenthesis are also listed in the NCBI HIV-1 interaction database (http://www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions/). Tsg101 was identified by candidate association [86] and in one siRNA screen [78]. Not all genes identified by uniquely by candidate gene analysis (Table 1) are listed.

Figure 5. Interdisciplinary approaches to identify host factors affecting HIV-1/AIDS

The complexity of host-HIV interactions and defenses require a multi-pronged, holistic approach to fully understand the biological systems that promote and impede HIV replication and pathogenesis. The integration of knowledge gained from the emerging technologies in genomics, transcriptomics, proteomics and epigenetics should lead to novel strategies for vaccine development and identify multiple, vulnerable targets for therapeutic intervention.