**29. Host coreceptor genes & insights on resistance to HIV infection**

A disproportionate transmission and distribution of HIV epidemic in the world has been observed with alarming rates in Sub Saharan Africa (SSA). Currently there is very little explanation for this observation of differences in susceptibility to HIV infection which could among other factors be attributable to variation in host genetics. Host genetic factors, including some polymorphisms in chemokine receptors and chemokine genes have been identified as having an impact on both HIV-1 infection and disease progression to death. Scientists have observed that despite multiple or repeated unprotected sexual exposures to HIV-1, some individuals remain HIV sero-negative. More so the discovery of long-term nonprogressors (LTNP) in HIV infection prompted further investigations to ascertain the role of host genetic factors in the progression of HIV infection to AIDS. Polymorphisms in these human chemokine receptor genes will therefore affect the evolution of HIV-1.

#### **30. CCR5 gene mutation**

Analysis of blood samples from infected persons and the repeatedly exposed but somehow uninfected have shown specific molecular differences within the coding and regulatory regions of chemokine receptors and coreceptors genes. There is a deletion of 32 base pairs from the coding region of CCR5 gene in the second ECL. In these individuals the 32-base deletion in the CCR5 gene results in a frame shift and truncation of the normal CCR5 protein which renders them uninfectable after exposure to CCR5 tropic HIV viruses. This aberrant protein has been associated with protection against HIV-1 infection in people who are homozygous for mutant genotypes. Thus individuals resistant to HIV infection inherit two mutated copies of the dysfunctional gene for CCR5 from either parent. Without functional coreceptors, HIV is not able to enter immune cells. Despite the strong protective effect conferred by congenital CCR5 deficiencies, a handful of infected *CCR5-Δ32* homozygotes have been reported, all invariably harboring CXCR4- dependent HIV-1 strains. The rare homozygous individuals that got infected by HIV have been shown to be through CXCR4 coreceptor mediated entry only. Interestingly it has been found that in such homozygous conditions there is no evidence of health/phenotypic impairment caused by the absence of functional CCR5 coreceptors. However, HIV-infected individuals who would have inherited a copy of the defective CCR5 gene from only one parent, heterozygotes for a Δ32 deletion (CCR5-wt/Δ32) are not protected against HIV-1 infection but are associated with a much slow progression to AIDS relative to those with two normal copies of the gene. Heterozygous individuals have lower plasma HIV RNA levels in the early years of infection, which gives them a medical advantage of delaying disease progression. Since these mutations do not account for all cases of resistance to HIV infection, scientists are looking for other possible host factors, including genetic defects involving other coreceptors. It was this protective property of CCR5∆32 against HIV infection that has prompted pharmaceutical companies to develop a CCR5 antagonist for clinical use in the treatment of HIV/AIDS. Studies have shown that inhibition of CCR5 coreceptor seems not to cause significant clinical harmful consequences yet surprising to date there has not been any description of natural genetic alteration in CXCR4 human gene, suggestive that mutations in this gene are incompatible with life.
