We have identified a truncated SR-family protein that has potent antiviral activity against HIV-1, HIV-2, and SIV, but no activity against MLV. Ectopic expression of the truncated SR-protein in human or mouse cells restricts the nuclear entry of HIV pre-integration complexes. Selection of HIV resistant to this factor leads to mutation in the virus capsid protein. Notably, these HIV mutants lose the ability to infect nondividing cells, and one mutation in particular interferes with HIV infection of terminally differentiated macrophages. We believe this to be a significant advance. In the era of molecular HIV studies, the discrete elements within HIV that are required for the infection of nondividing cells has proven to be a vexing question despite the sustained interest of gene therapists and HIV researchers. We are currently seeking cellular proteins targeted by the antiviral factor to better understand the machinery HIV interacts with in the infection of nondividing cells. We are also studying how the capsid mutations alter the biology of early HIV replication. In related work, we have also discovered dominant restrictions in human cells that interfere with HIV after entry but can be overcome by mutation of the viral core. These studies may provide new drug targets for antiviral therapy. Identification of HIV host cell factors will also enable the improvement of cell culture and animal models to study HIV transmission and replication. [Corresponds to KewalRamani Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Gres, Anna T; Kirby, Karen A; KewalRamani, Vineet N et al. (2015) STRUCTURAL VIROLOGY. X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability. Science 349:99-103
Maertens, Goedele N; Cook, Nicola J; Wang, Weifeng et al. (2014) Structural basis for nuclear import of splicing factors by human Transportin 3. Proc Natl Acad Sci U S A 111:2728-33
Koh, Yasuhiro; Wu, Xiaolin; Ferris, Andrea L et al. (2013) Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration. J Virol 87:648-58
Lee, Kyeongeun; Mulky, Alok; Yuen, Wendy et al. (2012) HIV-1 capsid-targeting domain of cleavage and polyadenylation specificity factor 6. J Virol 86:3851-60
Price, Amanda J; Fletcher, Adam J; Schaller, Torsten et al. (2012) CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS Pathog 8:e1002896
Ambrose, Zandrea; Lee, KyeongEun; Ndjomou, Jean et al. (2012) Human immunodeficiency virus type 1 capsid mutation N74D alters cyclophilin A dependence and impairs macrophage infection. J Virol 86:4708-14
Schaller, Torsten; Ocwieja, Karen E; Rasaiyaah, Jane et al. (2011) HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog 7:e1002439
Furtak, Vyacheslav; Mulky, Alok; Rawlings, Stephen A et al. (2010) Perturbation of the P-body component Mov10 inhibits HIV-1 infectivity. PLoS One 5:e9081
Lee, KyeongEun; Ambrose, Zandrea; Martin, Thomas D et al. (2010) Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 7:221-33
Krishnan, Lavanya; Matreyek, Kenneth A; Oztop, Ilker et al. (2010) The requirement for cellular transportin 3 (TNPO3 or TRN-SR2) during infection maps to human immunodeficiency virus type 1 capsid and not integrase. J Virol 84:397-406