HIV-1-Infected Long-Term Survivors in Hawaii:  Synergistic Effect of Mutated HIV-1 Co-Receptor CCR5 and Defective HIV-1 Accessory Protein Nef

             Differential susceptibility or resistance to HIV-1 infection is poorly understood.  Retrospective and prospective studies are now being conducted on individuals who remain uninfected despite high-risk exposure to HIV-1, such as HIV-1-seronegative prostitutes, long-term heterosexual or homosexual partners of HIV-1-infected people (discordant couples), as well as hemophiliacs who received large doses of HIV-1-tainted factor VIII/IX concentrates in the early 1980s.  Cellular, immunological and molecular data on HIV-1-infected long-term survivors (LTS) suggests that nef gene deletions and/or attenuation may be crucial to the survival of these patients.  Recently, two distinct chemokine receptors, CXCR4 and CCR5, have been identified as co-receptors for T-cell-tropic and macrophage-tropic HIV-1 isolates, respectively.  The homozygous 32-bp deletion mutant allele of CCR5 was found to protect 1% of a cohort of 1,955 high-risk behavior Caucasians from acquiring HIV-1 infection, whereas the heterozygotes (15-20% of Caucasian Americans) for this mutant allele were found to have delayed disease progression to AIDS.  We hypothesized that long-term survival in HIV-1-infected individuals may be achieved by synergism between a mutated CCR5 gene and a defective HIV-1 env or nef gene.

To test this hypothesis, we amplified and sequenced the complete HIV-1 nef gene and a 325-nucleotide region spanning the V3 loop of the gp120-encoding env gene from PBMC collected from 25 HIV-1-infected LTS and 10 rapid progressors (RP) with either mutated or normal CCR5 gene.  This project was conducted in collaboration with the HSPAMM program of the Hawaii State Department of Health.  Data are currently being analyzed.  These studies will help elucidate the in vivo pathogenesis of HIV-1 in our unique racial and multiethnic populations, and may serve to guide the design of effective therapeutic regimens and vaccines for HIV-1-infected individuals from Hawaii and the circum-Pacific region. 

In the future, we plan to isolate and study the viruses from LTS with CCR5 mutation with respect to virus growth kinetics, infectivity and usage of CCR5 and other HIV-1 co-receptors for virus entry and fusion.  In addition, plans are underway to study the association between HLA haplotypes of our HIV-1-infected, -uninfected and high-risk behavior populations to search for any genetic basis of HIV-1 susceptibility or resistance in ethnic minority groups. 

 

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