Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan
- Shigeru Nomuraa,
- Noriaki Hosoyab,
- Zabrina L. Brummec,d,
- Mark A. Brockmanc,d,
- Tadashi Kikuchia,
- Michiko Kogaa,
- Hitomi Nakamuraa,
- Tomohiko Koibuchie,
- Takeshi Fujiie,
- Jonathan M. Carlsonf,
- David Heckermanf,
- Ai Kawana-Tachikawaa,
- Aikichi Iwamotoa and
- Toshiyuki Miuraa*
- aDivision of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- bDepartment of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- cFaculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
- dBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
- eDepartment of Infectious Diseases and Applied Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- fMicrosoft Research, Los Angeles, California, USA
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Fig 1Correlation between plasma virus load, CD4+ T cell count, and year of HIV-1 diagnosis. No significant correlation between plasma HIV-1 load and the year of diagnosis (A) or the CD4+ T cell count and the year of diagnosis (B) was observed. Plasma virus loads and CD4+ T cell counts are based upon a single time point (date of blood sampling). Each dot represents a single individual (n = 177).
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Fig 2Validation of the origin of the gag-protease region in chimeric NL4-3 viruses. To verify the patient origin of each chimeric virus, a maximum-likelihood phylogenetic tree was constructed using plasma (red) and chimeric (blue) gag sequences. This tree includes 156 validated chimeric viruses that clustered with their original bulk sequences (two viruses were removed due to suspected contamination). The tree is rooted using the HIV-1 subtype A1 reference strain with GenBank accession number AF004885.
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Fig 3Correlation between replication capacity of chimeric NL4-3 and clinical markers of HIV infection. The correlation of replication capacity of chimeric NL4-3 with pVL (A) and CD4 T cell count (B) at the time of blood sampling (n = 156) is shown. A statistically significant positive correlation between RC and pVL was observed (R = 0.21, P = 0.0072).
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Fig 4Change in Gag-Protease-associated viral replication capacity over the epidemic in Japan. A statistically significant inverse correlation between year of diagnosis and replication capacity was observed in all subjects regardless of CD4 T cell count (n = 156) (A), only in subjects with a CD4+ T cell count of >200/μl (n = 145) (B), and only in subjects with a CD4+ T cell count of >300/μl (n = 100) (C). A similar tendency was observed when the analysis was limited to subjects with a CD4+ T cell count of >500/μl (n = 23) (D).
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Fig 5Temporal change in Gag-Protease-associated viral replication capacity of 55 sequences from a phylogenetic cluster. (A) Maximum-likelihood phylogenetic tree constructed using gag sequences from 156 Japanese individuals obtained in the present study and 263 individuals from other countries (randomly selected from the Los Alamos National Laboratory HIV sequence database). Purple, light blue, and blue branches, Japanese sequences with HIV diagnoses of 1999 or earlier, 2000 to 2004, and 2005 or later, respectively; green branches, sequences from the United States and Canada; yellow branches, sequences from other countries (Argentina, Australia, Brazil, China, Cuba, Cyprus, Denmark, France, Germany, Hong Kong, India, Italy, Jamaica, Myanmar, Netherlands, Russia, South Africa, South Korea, Spain, Taiwan, Thailand, and the United Kingdom). Reference strains (which include two reference sequences for each of the HIV-1 group M subtypes, as well as inferred ancestral sequences of the A, B, and C subtypes [obtained from the Los Alamos National Laboratory database]) are shown in black. NL4-3 is shown as red. The tree is rooted using the HIV-1 subtype A1 reference strain with GenBank accession number AF004885. A large cluster of Japanese sequences (n = 55) is indicated by the large red circle. (B) A significant inverse correlation between the replication capacity of chimeric viruses and year of HIV diagnosis for the viruses within this large Japanese cluster (n = 55).
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Fig 6Chimeric virus replication capacity is not related to genetic distance between the insert and backbone. Pairwise genetic distances between the gag nucleotide sequence of each insert (clinical isolate sequence) and backbone (wild-type NL4-3) were calculated as described in Materials and Methods. No statistically significant correlation between the genetic distance and replication capacity of chimeric NL4-3 was observed.
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Fig 7Relationship between common HLA alleles and chimeric virus replication capacity during early and late epidemic periods. To examine the potential impact of selection pressures by common HLA alleles in the Japanese population on the change in viral replication capacity, chimeric viruses were grouped according to year of HIV diagnosis (early [2002 or earlier] and late [2003 or later]), and associations between replication capacity and expression of particular HLA class I alleles were examined. Recombinant viruses from HLA-A*24-expressing hosts exhibited reduced RC before 2002 but not thereafter (A). However, such a phenomenon was not observed for other alleles investigated: A*02, B*40, and C*03 (B to D). Horizontal bars indicate the median values.
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