Malcolm A. Martin, M.D.

Chief, Laboratory of Molecular Microbiology
Chief, Viral Pathogenesis and Vaccine Section

Dr. Martin attended George Washington University and then received his M.D. from Yale University School of Medicine in 1962. Following clinical training in internal medicine at the University of Rochester School of Medicine, he became a research associate in the NIAID intramural program. An early leader in bringing molecular techniques to animal virology, Dr. Martin used DNA reassociation techniques to show that cells transformed by small DNA viruses (SV40 and mouse polyoma) could contain as few as one copy of newly integrated viral DNA.

Employing hybridization techniques and restriction endonuclease fragments of SV40 DNA, he generated the first transcription map of an animal virus in collaboration with the late Dan Nathans of the Johns Hopkins University School of Medicine. With Wally Rowe, he carried out risk assessment experiments with cloned polyomavirus DNA that established the safety of recombinant DNA. This led to a reduction in the physical containment required by the NIH guidelines then in place and permitted the molecular cloning of DNA from eukaryotic organisms and animal viruses to proceed.

Dr. Martin has been a major contributor and leader in human retrovirology, investigating both endogenous retrovirus elements in mouse and human DNAs and, since 1984, HIV. His laboratory constructed and made available one of the most widely used clones of HIV-1, NL4-3, in which all of the viral genes are intact and functional. His seminal contributions in the HIV-1 field include: 1) the initial structure/function studies of HIV-1 Vif and Vpu proteins; 2) analyses of the functional domains of the Gag matrix and gp120 Env proteins; and 3) genetic analyses of the LTR in the context of productive viral infections. In his recent work, SIV/HIV chimeric viruses (SHIVs) have been constructed that induce immunodeficiency in macaque monkeys. These viruses have been used in studies of HIV-1 pathogenesis and vaccine development.

Description of Research Program

My laboratory uses nonhuman primate models to investigate HIV-1 pathogenesis and develop effective prophylactic vaccines. Toward this end, we have constructed SHIVs that consistently induce a rapid, irreversible and systemic deletion of CD4+ T cells in rhesus monkeys within weeks of inoculation. Macrophage-tropic (M-tropic) SHIVs have been recently obtained, which utilize CXCR4, not CCR5, to enter both rhesus PBMC and alveolar macrophage. The pathogenic potential and cell targets of both T-tropic and M-tropic SHIVs during the very earliest phases of in vivo infections in inoculated macaques are currently under study.

Recent Data

Figure 1: Plasma neutralizing antibody titers and infection status of passively immunized rhesus monkeys challenged 24 hr post transfer with SHIV-DH12. The 99% protective titer in plasma deduced from this experiment is 1:38.

Figure 2: The highly pathogenic SHIV-DH12R causes rapid depletion of CD4 T cells in rhesus monkeys. Right panels: CD4 immunohistochemistry of mesenteric lymph nodes (LN) following SHIVDH12R infection. Left panels: In situ hybridization of mesenteric LNs using SIV/HIV-1 DNA probes.

Figure 3: The majority of SHIV-producing cells during the late stage of infection of rhesus monkeys are tissue macrophages. Confocal microscopy of virus positive (a and d), HAM56 (macrophage) positive (b) and CD3 (T cells) positive (e) cells. Fused images (c and f).

Figure 4: Five independent macrophage-tropic SHIVs isolated from late stage monkeys utilize CXCR4, not CCR5, to enter rhesus PBMC. Infections of rhesus PBMC were blocked with the indicated chemokine receptor inhibitors and the progeny virus released into the culture supernatants on day 5 was monitored.

Memberships

• Elected to The National Academy of Sciences, 1998
• Elected to The American Academy of Microbiology, 1998
• Member, NIH Central Tenure Committee
• ISI Highly Cited Researcher

Editorial Boards

• Virology
• Journal of Virology
• Associate Editor, Fields Virology, Fourth and Fifth Editions, 2001
• Scientific Advisory Committee, New England Regional Primate Center

Research Group Members

Tatsuhiko Igarashi, Ph.D., Research Fellow, tigarashi@niaid.nih.gov; Bernard Lafont, Ph.D., Visiting Fellow, blafont@niaid.nih.gov; Wendy Lee, B.S., Biologist, hmao@niaid.nih.gov; Yoshiaki Nishimura, Ph.D., Visiting Fellow, ynishimura@niaid.nih.gov; Reza Sadjadpour, M.S., Biologist, rsadjadpour@niaid.nih.gov; Ronald Willey, M.S., Biologist, rwilley@niaid.nih.gov.

Selected Publications

(View list in PubMed.)

Lafont BAP, Buckler-White A, Plishka RJ, Buckler C, Martin MA. Characterization of pig-tailed macaque classical MHC class I genes: Implications for MHC evolution and antigen presentation in macaques. J Immunol. 2003. 171: 875.

Igarashi T, Donau OK, Imamichi H, Dumaurier M-J, Sadjadpour R, Plishka RJ, Buckler-White A, Buckler C, Suffredini AF, Lane HC, Moore JP, Martin MA. Macrophage-tropic simian/human immunodeficiency virus chimeras use CXCR4, not CCR5, for infections of rhesus macaque peripheral blood mononuclear cells and alveolar macrophages. J Virol. 2003 77: 13042.

Nishimura Y, Igarashi T, Haigwood NL, Sadjadpour R, Donau OK, Buckler C, Plishka RJ, Buckler-White A, Martin MA. Transfer of neutralizing IgG to macaques 6 h but not 24 h after SHIV infection confers sterilizing protection: Implications for HIV-1 vaccine development. Proc Natl Acad Sci USA. 2003. 100: 15131.

Nishimura Y, Igarashi T, Donau OK, Buckler-White A, Buckler C, Lafont BAP, Goeken RM, Goldstein S, Hirsch VM, Martin MA. Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses. Proc Natl Acad Sci USA. 2004. 101: 12324.

Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin MA, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005. 434: 1093.

Nishimura Y, Brown CR, Mattapallil JJ, Igarashi T, Buckler-White A, Lafont BAP, Hirsch VM, Roederer M, Martin MA. Resting naïve CD4+ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques. Proc Natl Acad Sci USA. 2005. 102: 8000.

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