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APY248 HIV - U4 ggggg ”51.x” IIIIII w 5\l.§v1|‘ ll...

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Unformatted text preview: U4! ggggg ”51.x” IIIIII w. 5\l.§v1|‘ ) ll IN ‘ mmwcmfi 3H 36$me 5m mango ”mama“, F magnum 3mm? .3me on 39 mwnmm awmma ”.5 m“ mmmmfifimwfium gm. mmmofimaw $de Gm 5mm? muss? wmnmmm $3 B. 34.1,... "IV-w 0X03 900er 35‘ “3‘12; 583?: _ 990me as»? that must be negotiated by the virus in each host. In each instance, this requires a reequilibration of benefit (escape from CTL-mediated destruction) versus cost (effects of mutation on viral replicative capacity and pathogenicity). So where is this research endeavor head- ing, in both a conceptual and a practical sense? We offer three observations, each taken from a different perspective. First, these studies allow a glimpse of the conse- quences of uncontrolled, pandemic infec- tion in human populations. HIV is a highly successful pathogen in the sense that its extreme adaptive capacity allows it to cope with the vast majority of immune selection pressures that it encounters. Moreover, it is able to maintain sufficient pathogenicity in the face of these challenges, which prove lethal in most cases if left untreated. Although history suggests that many viruses are driven toward a more symbiotic relationship with their human hosts over time, evidence from the chimpanzee The permlssive host Low GCLaL1 Weak/narrow , "g HLA-restrtcled ,t-IIV NJ CTLresponse ::' TGFI ‘ h Mimental Weak HLA genome indicates that viruses such as SIV (the simian precursor to HIV- 1) are likely to have been responsible for a selective sweep of both HLA and CCR5 genetic diversity (6, 7). Thus, the virus is eventually limited to a relatively small reservoir of naturally protected hosts with limited genetic diver- sity as the result of a “bottleneck” effect in which nonprotective alleles do not survive. Second, these findings have immense importance for vaccine design and assess- ment (8). Through an appreciation of dynamic host-viral interactions, with their own temporal patterns and finely tuned bal- ance of cost versus benefit, we can begin to envisage the development of vaccines capa- ble of providing broad coverage against incoming (often highly adapted) viral strains in a genetically diverse vaccinee population. The nonrandom frequency dis- tribution of both HLA and chemokine receptor haplotype diversity in different demographic/ethnic populations (1, 9, 10) also indicates that genetic variation needs to PERSPECTIVES be considered on a global scale but that vac- cine design needs to be population-specific. . Finally, these data offer a conceptual challenge to both virologists and immunolo- gists to explore the intersections between these two disciplines. To take an overly sim- plistic view, it may be said that the virologist will tend to acknowledge the inherent varia- tion in viral populations while considering the host immune response to be relatively fixed. In contrast, the immunologist is more likely to appreciate the nuances of host immunology but underestimate the variabil- ity and adaptability of the pathogens to which it is exposed. Each viewpoint has its . benefits and weaknesses. But the willingness to negotiate complexity—and ultimately to recognize that order and constraint may operate in interacting systems that at first appear almost infinitely and chaotically vari- able—is likely to produce considerable divi- dends, particularly in relation to the develop- mentome vaccines. So far, we have devel- oped effective vaccines against relatively The nonpermlsslve host recognition (A ,. Strong/broad HLA-restricted CT L response APY 248 fHV/AIDS How does the human immunodeficiency virus (HIV) get into cells? How does it remain in the cell through successive cell divisions? How does the virus replicate (make more copies of itself)? CD4+ T lymphocytes are important in combating infections by inducing an immune response via activation of antibody producing B lymphocytes. Given this, what are the consequences of HIV entry into CD4+ T lymphocytes? What is the effect of this on an infected person’s ability to fight off other infections? How do different human polymorphisms lead to protection from infection by HIV or slower progression from HIV infection to full-blown AIDS? ...
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