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We show mathematically that progression to the strongest HIV-induced pathology requires evolution of the virus towards reduced replicative fitness<jats:italic>in vivo<\/jats:italic>. This counter-intuitive outcome can happen if multiple viruses co-infect the same cell frequently, which has been shown to occur in recent experiments. According to our model, in the absence of frequent co-infection, the less fit AIDS-inducing strains might never emerge. The frequency of co-infection can correlate with virus load, which in turn is determined by immune responses. Thus, at the beginning of infection when immunity is strong and virus load is low, co-infection is rare and pathogenic virus variants with reduced replicative fitness go extinct. At later stages of infection when immunity is less efficient and virus load is higher, co-infection occurs more frequently and pathogenic virus variants with reduced replicative fitness can emerge, resulting in T-cell depletion. In support of these notions, recent data indicate that pathogenic simian immunodeficiency virus (SIV) strains occurring late in the infection are less fit in specific<jats:italic>in vitro<\/jats:italic>experiments than those isolated at earlier stages. If co-infection is blocked, the model predicts the absence of any disease even if virus loads are high. We hypothesize that non-pathogenic SIV infection within its natural hosts, which is characterized by the absence of disease even in the presence of high virus loads, could be explained by a reduced occurrence of co-infection in this system.<\/jats:p>","DOI":"10.1098\/rspb.2007.0413","type":"journal-article","created":{"date-parts":[[2007,8,16]],"date-time":"2007-08-16T16:06:10Z","timestamp":1187280370000},"page":"2481-2491","source":"Crossref","is-referenced-by-count":33,"title":["Human immunodeficiency virus evolution towards reduced replicative fitness<i>in vivo<\/i>and the development of AIDS"],"prefix":"10.1098","volume":"274","author":[{"given":"Dominik","family":"Wodarz","sequence":"first","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, University of California321 Steinhaus Hall, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David N","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, New York University College of Dentistry847 Schwartz Building, 345 East 24th Street, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2007,7,31]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182000055360"},{"key":"e_1_3_2_3_1","doi-asserted-by":"crossref","unstructured":"Anderson R.M& May R.M Infectious diseases of humans. 1991 Oxford UK:Oxford University Press.","DOI":"10.1093\/oso\/9780198545996.001.0001"},{"key":"e_1_3_2_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1550"},{"key":"e_1_3_2_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10386"},{"key":"e_1_3_2_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.5.2262-2275.2001"},{"key":"e_1_3_2_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.7.4140-4149.2005"},{"key":"e_1_3_2_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307636100"},{"key":"e_1_3_2_9_1","doi-asserted-by":"publisher","DOI":"10.1006\/jtbi.1997.0548"},{"key":"e_1_3_2_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407498102"},{"key":"e_1_3_2_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0169-4758(96)80668-5"},{"key":"e_1_3_2_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1997.tb05106.x"},{"key":"e_1_3_2_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/419267"},{"key":"e_1_3_2_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.24.11744-11753.2000"},{"key":"e_1_3_2_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0297-212"},{"key":"e_1_3_2_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/8369"},{"key":"e_1_3_2_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/418144a"},{"key":"e_1_3_2_18_1","doi-asserted-by":"crossref","first-page":"6715","DOI":"10.1128\/JVI.73.8.6715-6720.1999","article-title":"Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection","volume":"73","author":"Kalams S.A","year":"1999","journal-title":"J. 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