The influence of MT-2 tropism on the prognostic implications of the Delta 32 deletion in the CCR-5 gene

Background: Long-term non-progression in HIV-l-infected patients has been reported to be associated with a 32 base-pair deletion (Delta 32) in one CCR-5 allele. The normal gene product acts as a coreceptor for HIV cell entry and is essential for infection of cells by non-syncytium-inducing and MT-2-negative HIV-1 strains. Methods: Forty individuals were studied, all of whom had been HIV-l-seropositive for a mean of 8 years. Results: Eight (20%) were heterozygous for the CCR-5 allele Delta 32 deletion. Six of these eight patients harboured MT-2-negative HIV-1 strains. Of these six, three were long-term non-progressors with a positive CD4 cell slope, not receiving antiretroviral treatment, whereas the other three were progressors (mean CD4 cell decline, 3.8 x10(6)/l per month) receiving antiretroviral combination therapy. Two of the eight patients with the Delta 32 deletion had MT-2-positive HIV-1 strains. Both had very rapid CD4 cell decline (6.7 and 7.6 x10(6)/l per month, respectively), despite triple antiretroviral therapy including a protease inhibitor. One of the patients with an MT-2-positive virus strain has suffered from Pneumocystis carinii bronchitis and the other from cytomegalovirus colitis. Conclusions: Disease progression may also occur in individuals with the coreceptor deficiency, especially in association with MT-2-positive HIV-1 strains. It is suggested that MT-2-positive HIV-1 enters cells through the CXC chemokine receptor-4 fusin coreceptor, thus circumventing the defective CC chemokine receptor-5 coreceptor. Various levels of expression of the wild-type CCR-5 gene and the gene with the Delta 32 deletion might explain variations in the disease progression in heterozygous patients with MT-2-negative HIV-1 strains.