The genome of HIV as noted in Figure 12.23 has a number of genes and genetic elements that involve both viral replication and the virus’s interaction with the infected cell. The predominant cell types infected by the virus through specific receptors are the “helper” (CD4) T cell (Chapter18) and the macrophage (Greenberg, 1992). As a retrovirus, the DNA copy integrated into the cell genome may remain dormant in the cell for extended periods, but in most instances the in- fected cell produces an altered array of its normal products as a result of the infection as well as producing multiple new virions with the ultimate demise of the cell (Shearer, 1998). However, there is no firm evidence that HIV viruses actually transform cells that they infect, and thus the carcinogenic influence of the virus is indirect, compromising the immune system and allowing infection by a variety of other oncogenic viruses as well as the expression of neoplasms nor- mally suppressed by the host immune system (Chapter 18). Therapy of AIDS has been directed toward preventing viral replication by use of inhibitors of the reverse transcriptase and the pro- tease, both required for viral synthesis. While dramatic therapeutic effects have been obtained, the genetic variation of HIV ultimately results in the development of a resistant viral strain
Figure 12.23 A. Genomic structure of HIV-1, indicating most of the known genes and their recognized primary functions. The 5′ and 3′ long terminal repeats (LTR) containing regulatory sequences recognized by various host transcription factors are also depicted. (Adapted from Greene, 1991, with permission of the author and publisher.) B. Genomic organization of HTLV-I. Long terminal repeats (LTR) and open reading frames are depicted with the translational start (ATG) and stop codons (dia- monds) indicated. (X) denotes intragenic region containing multiple short open reading frames. (After Ferreira et al., 1997, with permission of the authors and publisher.)
Figure 12.24 Estimated distribution of cumulative HIV infections in adults in various parts of the world as of mid-1993. (Adapted from Merson, 1993, with permission of the author and publisher.)
within the patient (Arts et al., 1998; Ridky and Leis, 1995). Since RNA viruses are deficient in specific proofreading mechanisms of the reverse transcriptase, replication errors that occur be- come immortalized, as can be seen in the genetic variation in viruses in patients in vivo (Hahn et al., 1986; Nowak et al., 1991). Mutation rates of the virus have been estimated at 3 × 10–4 to 3 × 10–5 per base per round of replication (Pezo and Wain-Hobson, 1997). Such rates of mutation are close to the maximum possible. Thus, it is not surprising that vaccines against the virus have been relatively unsuccessful in preventing infection in primates. These molecular facts bode ill for any lasting method of vaccination or therapeutic cure of the established disease, emphasizing the primary role of prevention in the control of AIDS in the world.