Host genes that affect progression of AIDS/HIV in India and novel gene therapeutic approaches against HIV

A multitude of host and viral factors play critical role in susceptibility to HIV-1 infection and its subsequent progression to AIDS. Various host factors involved in HIV-1 infection include the chemokine receptors CCR5, CX3CR1, their ligands, RANTES, SDF-1 and cytokines like IL-10, IL-4, among others. The CCR5Δ32 allele is the most important genetic factor known to confer resistance to HIV-1 infection. However, other mutations in CCR5, CX3CR1 and SDF-1 have also been identified in Indian population. Polymorphisms in DC-SIGN, MHC class-I and II molecules are also known to affect HIV-1 progression. These polymorphisms can be utilized as genetic markers for evaluating disease progression and developing effective therapeutics. The review also describes the development of anti-viral therapy, involving the use of catalytic nucleic acids like DNA-enzymes and ribozymes and the expression of ribozymes and si-RNA using lentiviral vectors for stem cell based anti-HIV therapy

Genetic and functional characterization of human immunodeficiency virus type 1 VprC variants from north India: presence of unique recombinants with mosaic genomes from B, C and D subtypes within the open reading frame of Vpr

The human immunodeficiency virus type 1 (HIV-1) epidemic in India is predominantly caused by genetic subtype C, though other minor subtypes have also been reported. One of the major accessory proteins of HIV-1, namely Vpr, is known to influence key steps in viral replication, cell cycle progression, promoter activation, apoptosis and pathogenesis. Therefore, we carried out a genetic and functional analysis of the Vpr variants from eight HIV-1-infected individuals from north India. The sequence analyses revealed that six of eight samples clustered with ancestral subtype C. Remarkably, five of these showed a conserved and region-specific L64P mutation, located in the predicted third a-helix. This change adversely affected their ability to activate the HIV-1 long terminal repeat promoter without compromising their ability to cause apoptosis. Bootscan, phylogenetic and SimPlot analysis of the remaining two samples (VprS2 and A6) revealed very interesting mosaic genomes derived from B, C and D subtypes. The N-terminal half of the VprS2 gene consisted of genomic segments derived from subtypes B/D, C and D but the C-terminal half was derived predominantly from subtype C. Interestingly the N-terminal half of sample A6 also showed similar B/D, C and D inter-subtype recombinant structure but the C-terminal half was entirely derived from the consensus B subtype. Multiple breakpoints in a short stretch of 291 nt encoding the Vpr gene strongly suggest that this region is a potential hot-spot for the formation of inter-subtype recombinants and also highlight the importance of the rapidly evolving HIV-1 epidemic in the north Indian region due to multiple genetic subtypes