Molecular Biology and Pathogenesis of HIV-1
AIDS is currently a leading cause of death in the United States and a major cause of morbidity and mortality worldwide. The latest estimates indicate that about one million Americans and over thirty million people worldwide are infected with HIV-1. Despite the introduction of better treatments for AIDS in the developed world, there is still a need for research and development relating to the mechanisms of HIV-1 pathogenesis and new methods of inhibiting the development of AIDS.
During the last few years we have focused our efforts on understanding the pathogenesis of CCR5 tropic strains of HIV-1 (R5 HIV-1) and on the selection for and maintenance of R5 HIV-1 following viral transmission, and during the first few years of infection. These topics are of crucial importance to an understanding of HIV-1 pathogenesis since R5 HIV-1 is predominant in infected individuals. We use normal human lymphocytes, tonsil and lymph node organ cultures to realistically study HIV-1 infection of the mature immune system. We also study HIV-1 infection of the thymus, an important aspect of AIDS, using SCID mice bearing human thymic grafts (SCID-hu mice), and thymic organ culture. These systems, which maintain the complexity of lymphoid tissue, are ideal for our studies of HIV-1 pathogenesis since they accurately mimic the in vivo situation.
When HIV-1 is isolated from patients early in the course of infection it is typically CCR5 tropic, replicates relatively poorly and is not very cytopathic. In contrast, HIV-1 isolated from AIDS patients may be R5, dual tropic (R5X4) or CXCR4 tropic (X4), but usually replicates more efficiently and is more cytopathic. We have taken advantage of this evolution of HIV-1 within infected individuals to map the determinants of HIV-1 mediated cytopathic effects (CPE) of AIDS associated R5 HIV-1. We are also determining the mechanisms of HIV-1 mediated CPE on infected cells and bystander cells. We have made progress in this area using thymic organ culture.
Another recent focus of our work has been to understand why R5 HIV-1 is selected following viral transmission, even when the transmitting individual also possesses the more pathogenic R5X4 or X4 HIV-1 types. A related question is why R5 HIV-1 strains are maintained during the long asymptomatic phase of HIV-1 infection when R5X4 or X4 mutants may frequently arise. Our recent data strongly suggest that HIV-1 mediated signalling through CCR5 allows infection of resting memory CD4+ T cells, which are crucial targets of HIV-1 infection.
Other interests in the lab include the mechanisms of action of the innate antiviral proteins known as defensins. Several defensins block HIV-1 replication by mechanisms that are not well charcterized. Understanding these mechanisms may shed light on viral pathogenesis and lead to new treatments for AIDS.
Cervantes-Garcia D, Rojas-Martinez A and Camerini D: An XMRV derived retroviral vector as a tool for gene transfer. Virol J. 2011 Jun 8;8:284.
Seidel A, Ye Y, de Armas LR, Soto M, Yarosh, W, Marcissin R, Tran P, Selsted M and Camerini D: Cyclic and Acyclic Defensins Inhibit Human Immunodeficiency Virus Type-1 Replication by Different Mechanisms. PLoS One 5(3) e9737, 2010.
Olivieri K, Scoggins RM, Broderick B, Chmura M, Alexander M, Hammarskjold M-L, Rekosh D and Camerini D: Nef does not contribute to replication differences between R5 pre-AIDS and AIDS HIV-1 clones from patient ACH142. Retrovirology, 5, 42, 2008.
Choudhary S, Vrisekoop N, Jansen C, Otto S, Schuitemaker H, Miedema F and Camerini D: Low Immune Activation Despite High Levels of Pathogenic HIV-1 Results in Long-Term Asymptomatic Disease. J Virol. 81, 8838-8842, 2007.
Olivieri K, Scoggins RM, Bor Y-c, Matthews A, Mark BD, Taylor JR Jr, Chernauskas D, Hammarskjold M-L, Rekosh D and Camerini D: The envelope gene is a cytopathic determinant of CCR5 tropic HIV-1. Virology 358, 23-38, 2007
Choudhary S, Walker R, Powell D, Planelles V, Walsh C and Camerini D: CXCR4 tropic HIV-1 induces apoptosis in immature infected thymocytes by inducing factors involved in negative selection, Virology 352, 268-284, 2006.
Ye Y, De Leon J, Yokoyama N, Naidu Y and Camerini D: DBR1 siRNA inhibition of HIV-1 replication. Retrovirology 2, 63, 2005.
Choudhary S, Choudhary N, Kimbrell K, Colasanti J, Ziogas A, Kwa D, Schuitemaker H and Camerini D: R5 HIV-1 infection of fetal thymic organ culture induces cytokine and CCR5 expression. J Virol. 79, 458-471, 2005.
Immunology and Pathogenesis
Center for Virus Research, Immunology Institute