Friday, January 13, 2012

The Challenge of HIV-1 Subtype Diversity

Neary 27 years after the first reported cases of the acquired immunodeficiency syndrome (AIDS) and 25 years after the discovery of the etiologic agent, effective control of the AIDS pandemic remains elusive. At the root of this challenge is the molecular pathogenesis of human immunodeficiency virus (HIV) type 1 (HIV-1), a virus that has evolved a number of mechanisms to elude immune control. Among the most prominent of these are the heavy glycosylation of the external glycoprotein, which protects neutralization epitopes; the virus' direct targeting of the CD4 molecule expressed by the key T lymphocyte in immune orchestration; integration into the host-cell genome, which implies that cells that are not killed are infected permanently; and the potential of the virus to mutate and therefore evade
the host immune system (mutational escape).1,2 This last mechanism results in a remarkable degree of viral diversity within HIV-1 and its rapid adaptation, in response to both immune activity and antiretroviral therapy. Over the past decade, advances in sequencing technology and expanded disease surveillance have allowed researchers to characterize the variation in HIV-1 within individual patients and around the world. Origin of HIV and Mechanisms of HIV Diversity The origin of HIV-1 among nonhuman primates has been traced to a simian virus, SIVcpz, which infected several geographically isolated chimpanzee communities in southern Cameroon. This HIV-1 progenitor probably was passed from chimpanzees to human hunters through bloodborne transmission. Phylogenetic analysis of HIV-1 and related viruses from nonhuman primates suggests that three independent transmission events early in the 20th century spawned three HIV-1 groups: major (M, between 1915 and 1941), outlier (O), and nonmajor and nonoutlier (N).3,4 Although strains related to the M and N groups have been found in chimpanzees, recent evidence suggests that group O HIV-1 may have originated in gorillas, in which the closest relatives of this group have been identified.5 It is speculated that the virus then spread among humans along the Congo River into Kinshasa, Zaire, where the earliest documented case of HIV-1 infection (with group M strain) in humans has been traced to a blood sample from 1959.6 HIV has several intrinsic mechanisms that ensure rapid viral evolution. The reverse transcriptase of HIV lacks proofreading activity, the ability to confirm that the DNA transcript it makes is an accurate copy of the RNA code, and confers a mutation rate of approximately 3.4x10–5 mutations per base pair per replication cycle. Since the HIV genome is an estimated 104 base pairs in length and the baseline rate of viral production is approximately 1010 virions per day, millions of viral variants are produced within any infected person in a single day.7 HIV-1 recombination can lead to further viral diversity and occurs when one person is coinfected with two separate strains of the virus that are multiplying in the same cell (Figure 1).8,9 The initial view that the virus is classifiable into distinct subtypes or clades now needs to reflect the reality of a dynamic genetic evolutionary process, through which new HIV-1 strains are constantly emerging. The resultant viral diversity has implications for possible differential rates of disease progression, responses to antiretroviral therapy (including the development of resistance), and vaccine development.

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