Host Genetics, Coreceptor Function, Host Susceptibility to HIV Infection, and Disease Progression

Abstracts & Commentary

By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley, Medical, Clinical Professor of Medicine, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron, and is on the speaker’s bureau for Pfizer/Agouron.

Synopsis: At least 2 CCR5 variants that modify coreceptor properties have been recently recognized in individuals from Southeast Asia. Four single nucleotide polymorphisms (SNPs) and specific haplotypes in the IL2 and CCR2/CCR5 genes were significantly associated with HIV-1 infection susceptibility. A third paper elucidates the likely mechanism by which GB virus C (GBV-C) may result in prolonged survival in HIV-positive individuals.

Sources: Capoulade-Metay C, et al. New CCR5 Variants Associated with Reduced HIV Coreceptor Function in Southeast Asia. AIDS. 2004;18:2243-2252; Shrestha S, et al. Behavioral Risk Exposure and Host Genetics of Susceptibility to HIV-1 Infection. J Infect Dis. 2006;193:16-26; Xiang J, et al. South African GB Virus C Isolates: Interactions Between Genotypes 1 and 5 Isolates and HIV. J Infect Dis. 2005;192:2147-2151.

The laboratory group from the Pasteur Institute and inserm screened for CCR5 coding region polymorphisms in 3 groups of Vietnamese subjects, including 47 HIV-1 infected intravenous drug users (IDUs), 50 highly HIV-1 exposed but seronegative IDUs, and 37 HIV-1 unexposed seronegative individuals. Five CCR5 coding region variants were identified. Two variants had previously been identified (G106R, R223Q) and 3 were identified in this study (S185R, I254T, and C269F). S185R and I254T variants had receptor and coreceptor activities comparable to wild type. However, C269F and G106R are poorly expressed at the cell surface and weakly bind macrophage inflammatory protein 1B (MIP-1B) and RANTES and display reduced coreceptor efficiency. G106R is a nonconserved amino acid substitution which produces alteration of residue hydrophobicity and was only found in the HIV-negative groups. C269F is a major substitution which disrupts the disulphide bond linking the third extracellular loop of CCR5 to the N-terminus.

The second paper lead by a team of researchers at NCI and Johns Hopkins conducted a nested case-control study of African Americans, including 266 HIV-1 seroconverters and 532 seronegative controls, which examined the association between 50 SNPs in 9 candidate genes (CCR5, CCR2, RANTES, MIP1A, MCP2, IL10, IFNG, MCSF, and IL2). Four SNPs (CCR2-V64I, CCR5-2459, MIP1A+954, and IL2+3896) and specific haplotypes in the IL2 and CCR2/CCR5 regions were associated with HIV-1 infection susceptibility using different modeling techniques.

The last paper from a research group at the University of Iowa collaborating with a group in South Africa identified GBV-C virus isolates from genotypes 1, 2, and 5 in South African blood donors. GBV-C genotype 1 and genotype 5 isolates grew in vitro in lymphocyte culture, inhibited X4 and R5 tropic HIV-1 isolates, and induced RANTES and stromal-derived factor 1 (SDF-1) chemokines in vitro.

Commentary

Host genetics have long been believed to play a major role in host susceptibility to infection by HIV, as well as the great variability between individuals in rates of disease progression. Approximately 10 years ago it was discovered that a 32 base pair deletion in the CCR5 gene (found in 10% of individuals of European descent) confers at least partial protection against HIV disease progression in heterozygotes and essentially complete protection against de novo infection in homozygotes.1-3 This variant is not seen in Asians, hence, the potential importance of the 2 CCR5 variants identified in the first paper. Unfortunately, the sample size examined in this study was too small to draw firm conclusions about the role of these variants in vivo. The second paper, which examined an African American population, also presents intriguing preliminary data on genetic variants in HIV-1 coreceptors and various chemokines and their relationship to susceptibility to HIV infection.

Finally, it was observed almost a decade ago that the nonpathogenic flavivirus, GBV-C, when coinfecting HIV-1 infected individuals, may result in slowing of HIV disease progression, higher CD4 counts, and lower viral loads than observed in non-GBV-C-infected patients.4 However, other studies have not seen this relationship.5 The paper by Xiang and colleagues helps explain these discrepancies by difference in GBV-C genotype in the HIV-coinfected populations studied, and, importantly, demonstrates a plausible biological cause for this protection.

While much research remains to be done to allow a full understanding of host factors and susceptibility to HIV infection and disease progression, it is nice to see such progress being made. Already, small molecule inhibitors of CCR5 (and CXCR4) have entered clinical efficacy trials. It is hoped that additional therapeutic targets will be identified in the coming decade as a result of this kind of research.

References

  1. Samson M, et al. Resistance to HIV-1 Infection in Caucasian Individuals Bearing Mutant Alleles of the CCR-5 Chemokine Receptor Gene. Nature. 1996;382:722-725.
  2. Liu R, et al. Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection. Cell. 1996;86:367-377.
  3. Meyer L, et al. Early Protective Effect of CCR-5 Delta 32 Heterozygosity on HIV-1 Disease Progression: Relationship with Viral Load. The SEROCO Study Group. AIDS. 1997;11:F73-F78.
  4. Polgreen PM, et al. GB Virus Type C/Hepatitis G Virus: A Non-pathogenic Flavivirus Associated with Prolonged Survival in HIV-infected Individuals. Microbes Infect. 2003;5:1255-1261.
  5. Sathar MA, et al. GB Virus C/Hepatitis G Virus Infection in KwaZulu Natal, South Africa. J Med Virol. 1999;59:38-44.