Genetic determinants of HIV-1 infection and its manifestations

The human immunodeficiency virus type 1 (HIV-1), which has become pandemic within a single generation, has encountered an immune system in which genetically encoded elements have evolved gradually under different environmental pressures in diverse populations. Important heritable differences in genes that alter susceptibility to HIV-1 infection or the rate of deterioration of immunity, or both, have been discovered in cohorts carefully defined for intensity of exposure to the virus, viral subtype characteristics, and onset and course of infection. For the highly polymorphic human leukocyte antigen (HLA) antigen processing and presenting system, the principle that small contributions of multiple interactive HLA marker combinations (primarily in the class I pathway) significantly modulate the course of HIV-1 infection has now been confirmed in several independently evaluated groups of patients. Variants of HLA genes probably also play some role in the acquisition of infection by the various routes of transmission. Genes for an elaborate set of circulating chemokine molecules and their cell-surface receptors clearly regulate cell attachment and penetration of HIV. Certain allelic forms of one, the CCR5 gene, alter susceptibility to infection and the rate of progression of disease; in the homozygous state, a deleted form (Delta 32 CCR5) strongly protects against infection, and in infected heterozygotes, it slows the disease process somewhat. Mutants in genes of other chemokine system components further differentiate the response to infection, and frequencies of these forms vary between and within races. Work relating additional genetic markers to HIV infection or disease is at earlier stages. Dissecting the effects of multiple variants in complex gene systems will clearly require organized comprehensive approaches in considerably larger populations than have typically been assembled.