The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

One concern is to what extent the subset of NHANES participants evaluated for HCV infection and diabetes was representative of the entire NHANES population sample. This is a significant question because the overall NHANES sample is considered the best representation of the general population of the United States, a collection of subjects free of the bias usually present in clinic-based investigations. Thus, it was reassuring that the subset of NHANES that could be evaluated for HCV infection and diabetes was both large (9,841 persons) and similar to other NHANES members with respect to many factors, including all recognized correlates of both HCV infection and diabetes. 1 This representation essentially eliminates the potential for selection bias. Another strength of the NHANES analysis is the careful testing for HCV infection performed by the Hepatitis Branch at the Centers for Disease Control and Prevention. Because HCV infection was assessed by second-generation enzyme immunoassay and confirmed by supplemental antibody testing, there is no doubt that most positive results reflect true HCV exposure. Indeed, in the subset tested for both HCV antibody and RNA, HCV RNA was detected in all but 26%, the percent one would expect to have cleared infection if all antibody-positive subjects had been previously infected. 3 Dr. Everhart raised the question of whether the antibody testing should be the main determinant of HCV or if the analysis should be restricted to persons with both HCV antibody and RNA. 2 If one were convinced that the association exists exclusively because ongoing HCV infection caused diabetes, it would have been appropriate to restrict the analysis to persons whose blood contained both HCV antibodies and RNA. Because too little is known about the pathogenesis and temporal sequence of HCV infection and diabetes to make these assumptions, the analysis initially was presented using antibody testing as the marker of HCV exposure. Nonetheless, Dr. Nainan and coworkers at the Centers for Disease Control and Prevention generously provided the HCV RNA data. For the subset for whom there is HCV RNA testing, the age-adjusted odds of type 2 diabetes in persons with HCV RNA and antibody was 2.48 (95% CI 1.23-5.01) compared with 0.98 for persons with HCV antibody but not RNA. If confirmed , these data are not consistent with the conjecture that diabetes leads to HCV infection, but instead favor hypotheses suggesting that persistent HCV infection is associated with the subsequent development of diabetes. Another important discovery in the analysis of HCV infection and type 2 diabetes in NHANES was the difference in the magnitude and direction of the association in persons of relatively young ages. Type 2 diabetes is a clinically heterogeneous syndrome that, according to the Cecil Textbook of Medicine, "typically appears after the age of 40 years." 4 In NHANES III, type 2 diabetes was not associated with HCV infection in persons less than 40 years of age. 1 Type 2 diabetes may be a different condition when it mani...

A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Major histocompatibility complex (MHC) genes (HLA in humans) regulate the immune response to foreign antigens. Molecular and serologic techniques were used to identify products of HLA class I, class II and transporter (TAP) genes (also part of the MHC) in homosexual seroconverters to human immunodeficiency virus type 1 (HIV-1). Comprehensive statistical analysis produced an HLA profile that predicted time from HIV-1 infection to the onset of AIDS. The profile was developed in a cohort of 139 men and evaluated in a second unrelated cohort of 102 men. In the evaluation cohort, the profile discriminated a sixfold difference between groups with the shortest and longest times to AIDS (P = 0.001). These findings support current theory about control of antigen processing by HLA genes and have implications for immunopathogenesis of HIV-1 and other infections.

The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.