Box HIV and AIDS

The first cases of AIDS were reported in 1981, an immunodeficiency syndrome characterized by depletion of a specific type of T cell, opportunistic infections (such as pneumonia due to the fungus Pneumocystis carinii, and infection with cytomegalo-virus and mycobacteria), and specific cancers (such as Kaposi's sarcoma and B cell lymphoma). How was HIV identified as the agent responsible for AIDS? Gallo and Monagnier (2003) describe how a specific subgroup of T cells carrying the CD4 surface antigen were noted to be significantly reduced in patients with AIDS, suggesting an agent specifically targeting CD4+ T cells such as the recently identified human T cell leukaemia virus (HTLV). The modes of transmission of HTLV through blood and sexual contact, and between mother and infant, mirrored what was known about the epidemiology of AIDS, and an AIDS-like wasting syndrome was seen in animal models of lymphotropic retrovi-ruses, leading to a search for HTLV-like viruses in AIDS patients. This culminated in the isolation of HIV, and establishment of a causal relationship with AIDS that was broadly accepted by the scientific community by 1984. The epidemiological data that followed the development and application of a specific blood test for HIV, and the clinical efficacy of drugs inhibiting HIV enzymes, supported this view. In fact there are at least two types of HIV: HIV-1 which is more virulent and responsible for most cases of AIDS worldwide, and HIV-2 which is more geographically restricted and endemic in West Africa.

The origin of HIV lies in simian immunodeficiency viruses (SIV) found in primates (Heeney

(B)

Figure 14.1 Overview of HIV-1 entry and replication in host cells. (A) The virion of HIV-1 contains integrase (O), protease (O) and reverse transcriptase (O) enzymes together with two copies of the RNA genome. (B) Viral glycoproteins in the viral envelope interact with host cell surface receptor and coreceptor proteins, the envelope then fuses with the cellular membrane, and viral genetic material enters the cytoplasm as a nucleoprotein core. The virus uses the host cell's cellular proteins and machinery, together with some specific viral proteins present in the nucleoprotein core, to replicate. The two copies of the viral RNA genome are reverse transcribed into DNA, transported into the nucleus, and become integrated into host DNA. The integrated proviral DNA is then transcribed and the viral mRNAs are processed and exported from the nucleus. Following translation, viral proteins such as Tat and Rev further amplify transcription of proviral DNA and transport out of the nucleus while late proteins such as Gag, Pol, and Env are assembled with viral RNA into virions, which escape the host cell at budding sites.

Figure 14.1 Overview of HIV-1 entry and replication in host cells. (A) The virion of HIV-1 contains integrase (O), protease (O) and reverse transcriptase (O) enzymes together with two copies of the RNA genome. (B) Viral glycoproteins in the viral envelope interact with host cell surface receptor and coreceptor proteins, the envelope then fuses with the cellular membrane, and viral genetic material enters the cytoplasm as a nucleoprotein core. The virus uses the host cell's cellular proteins and machinery, together with some specific viral proteins present in the nucleoprotein core, to replicate. The two copies of the viral RNA genome are reverse transcribed into DNA, transported into the nucleus, and become integrated into host DNA. The integrated proviral DNA is then transcribed and the viral mRNAs are processed and exported from the nucleus. Following translation, viral proteins such as Tat and Rev further amplify transcription of proviral DNA and transport out of the nucleus while late proteins such as Gag, Pol, and Env are assembled with viral RNA into virions, which escape the host cell at budding sites.

et al. 2006). HIV-1 is believed to have evolved on at least three separate occasions from a particular SIV strain, SIVcpz, found in one subspecies of chimpanzee (Pan troglodytes troglodytes) whose natural habit includes southern Cameroon (Keele et al. 2006). HIV-2 appears to have crossed between species on many occasions and has its origin in SIVsm found in sooty mangabeys (Cercocebus atys) (Santiago et al. 2005). HIV is a an RNA virus that encodes reverse transcriptase, an enzyme which enables the RNA genome to be copied into DNA within the infected cell and become integrated into the genomic DNA of the host cell (Fig. 14.1). Within the retrovirus family, HIV is a member of the lentivirus group and related to a number of animal lentiviruses which also infect immune cells and result in immunodeficiency and slow progressive disorders.

However, not all people exposed to HIV become infected, and those who do, progress to AIDS at significantly different rates (Box 14.2). Studies of highly exposed yet persistently seronegative individuals together with prospective cohort studies of groups at risk of HIV exposure have proved highly informative in resolving genetic determinants of disease susceptibility and progression (Kulkarni et al. 2003; O'Brien and Nelson 2004). Genetic variation in genes encoding proteins involved in HIV entry to cells, barriers to retroviral infection within cells, cytokines, and cell mediated and innate immunity have all been shown to be involved in HIV infection and development of AIDS (Fig. 14.2) (O'Brien and Nelson 2004; Heeney et al. 2006). In this chapter some of this remarkable work is reviewed, highlighting the complex relationship between human genetic diversity and viral infection, and the insights such analysis gives into the current AIDS pandemic and our evolutionary history.

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