HIV-1 and the central nervous system: HIV-1 enters the CNS and causes encephalitis and neurologic disease ranging from minor cognitive/motor disorders to severe dementia (HIV-associated dementia or HAD). In the brain, HIV-1 productively infects microglia (resident brain macrophages) and perivascular macrophages, which express low levels of the primary receptor for HIV-1, CD4. Multinucleated giant cells or syncytia (resulting from fusion of infected and uninfected cells) are the hallmark of HIV encephalitis. Perivascular macrophages have some turnover and are replenished by monocyte migration across the blood-brain barrier (probably the main route of entry of HIV-1 into the brain), while microglia are very long-lived cells with extremely low turnover that support viral replication for extended periods of time, and it has been hypothesized that HIV-1 may adapt in vivo to replication in microglial cells.
Schematic depiction of HIV neuroinvasion and syncytia formation (González-Scarano and Martín-García, Nature Reviews Immunology 2005; 5:69-81).
Our laboratory is currently interested in the phenotypic characterization of HIV-1 primary isolates/envelope glycoproteins derived from CNS and peripheral autopsy tissues of HIV-1-positive individuals with and without neurological disease. Using a combination of virology, cell and molecular biology, and biochemical techniques, we want to determine CD4 and co-receptor requirements, envelope conformation, sensitivity to various inhibitors and binding to receptors, with the goal of increasing our understanding of the process of in vivo HIV-1 adaptation to replication in the CNS. We have found that brain-derived envelopes require lower levels of CD4 to efficiently mediate fusion and infection (as hypothesized), and are surprisingly less sensitive to synthetic peptide fusion inhibitors, a new class of antiviral drugs targeting the HIV-1 envelope glycoprotein-mediated fusion.
In addition, we are interested in conducting experiments that will allow us to determine whether the viral envelope glycoproteins from different tissues determine the viral fitness of each isolate in relevant CNS cell types. By producing isogenic recombinant viruses, we will compare envelope-determined replication, fusogenicity and pathogenicity in cultures of various CNS and non-CNS cell types.
Our laboratory also wants to evaluate the relationship between neurotropism and neurotoxicity, since we are now able to directly compare the pathogenic effects of paired viruses, as well as their envelope glycoproteins in various forms, from CNS and peripheral tissues. We plan to study the potential direct mechanisms involved in HIV-1 neurotoxicity and bystander or indirect mechanisms, to determine their contribution to HIV neuropathogenesis and potentially identify new therapeutic targets. In addition, the neurotropism of HIV-1 has been almost exclusively studied to date with isolates belonging to subtype B (the most prevalent in the U.S. and Western Europe). Thus, we are expanding our research into other viral subtypes and especially subtype C, since it is the most prevalent subtype in Southern Africa and the Indian subcontinent, and it is also responsible for a majority of new infections worldwide.
We are focused on how TLR stimulation regulates microRNA expression profiles and the subsequent effects on cellular proteins that play a role in the viral life cycle.
HIV-1, Toll-like receptors (TLRs) and microRNAs: We are increasingly focusing our attention as well in trying to define how some components of the innate immune responses (especially TLRs and microRNAs) in monocyte/macrophages and dendritic cells can modulate their susceptibility to productive HIV-1 infection. We are specifically focusing on understanding how TLR stimulation regulates microRNA expression profiles and the subsequent effects on expression of cellular proteins that have been shown to play a role, or might potentially do so, either positively or negatively, at various steps of the viral life cycle. In this context, we have found a remarkable anti-HIV-1 effect of microRNA-155 in human macrophages, and we are further exploring these interactions that could potentially lead to novel preventive/therapeutic approaches.
Finally, in collaboration with Dr. Simon Cocklin (Dept. of Biochemistry and Molecular Biology), we are exploring the potential antiviral effect of small molecules that he has identified with the goal of targeting the matrix and capsid proteins of HIV-1, which could potentially result in novel additions to the therapeutic armamentarium against HIV-1.
Selected Publications (See all Julio Martin-Garcia's publications in PubMed.)
"A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages."
G Swaminathan, F Rossi, LJ Sierra, A Gupta, S Navas-Martín, and J Martín-García.
PLoS Pathogens, 8:e1002937, doi:10.1371/journal.ppat.1002937; 2012.
"Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 Capsid"
S Kortagere,N Madani, MK Mankowski, A Schön, I Zentner, G Swaminathan, A Princiotto, K Anthony, A Oza, LJ Sierra, SR Passic, X Wang, DM Jones, E Stavale, FC Krebs, J Martín-García
Journal of Virology, Antimicrobial Agents and Chemotherapy. 86:8472-8481, 2012 .
"Antiviral breadth and combination potential of peptide triazole HIV-1 entry inhibitors."
K McFadden, P Fletcher, F Rossi, F Kantharaju, M Umashankara, V Pirrone, S Rajagopal, H Gopi, FC Krebs, J Martín-García, RJ Shattock, and IM Chaiken.
Antimicrobial Agents and Chemotherapy 56: 1073-1080, 2012.
"The V1-V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and altered sensitivity to entry inhibitors"
F. Rossi, B. Querido, M. Nimmagadda, S. Cocklin, S. Navas-Martín, and J Martín-García
Retrovirology, 5: 89, 2008
"Broad-spectrum anti-HIV potential of a peptide HIV-1 entry inhibitor"
S. Cocklin, H. Gopi, B. Querido, M. Nimmagadda, S. Kuriakose, C. Cicala, S. Ajith, S. Baxter, J. Arthos, J. Martín-García, and I.M Chaiken
Journal of Virology, 81: 3645-3648, 2007
"HIV-1 tropism for the central nervous system: brain-derived envelope glycoproteins with lower CD4-dependence and reduced sensitivity to a fusion inhibitor"
J. Martín-García, W. Cao, A. Varela-Rohena, M.L. Plassmeyer, and F. González-Scarano
Virology, 346: 169-179, 2006
"Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology"
M.F. Chen, S. Westmoreland, E.V. Ryzhova, J. Martín-García, S.S. Soldan, A. Lackner, and F. González-Scarano
Journal of Neurovirology, 12: 73-89, 2006
"Interaction with CD4 and antibodies to CD4-induced epitopes of the envelope gp120 from a microglia-adapted human immunodeficiency virus type 1 isolate"
J. Martín-García, S. Cocklin, I.M. Chaiken, and F. González-Scarano
Journal of Virology, 79: 6703-6713, 2005
"The neuropathogenesis of AIDS"
F. González-Scarano and J Martín-García
Nature Reviews Immunology, 5: 69-81, 2005
"Chemokine receptors in the brain: their role in HIV infection and pathogenesis"
J. Martín-García, D.L. Kolson, and F. González-Scarano
AIDS,16: 1709-1730, 2002
"Differential CD4/CCR5 utilization, gp120 conformation, and neutralization sensitivity between envelopes from a microglia-adapted human immunodeficiency virus type 1 and its parental isolate"
J. Martín-García, C.C. LaBranche, and F. González-Scarano
Journal of Virology, 75: 3568-3580, 2001
"Interactions between HIV-1 gp120, chemokines, and cultured adult microglial cells"
A.V. Albright, J. Martín-García, M. O'Connor, and F. González-Scarano
Journal of Neurovirology, 7: 196-207, 2001
"Determinants of syncytium formation in microglia by human immunodeficiency virus type 1: role of the V1/V2 domains"
J.T.C. Shieh, J. Martín-García, G. Baltuch, M.H. Malim, and F. González-Scarano
Journal of Virology, 74: 693-701, 2000
"Antiviral effect of amantadine and interferon α-2a against hepatitis C virus on peripheral blood mononuclear cells from chronic hepatitis C patients"
J. Martín-García, S. Navas, M. Fernández, M. Rico, M. Pardo, J.A. Quiroga, F. Zahm, and V. Carreño
Antiviral Research, 42: 59-70, 1999
"In vitro infection of human peripheral blood mononuclear cells by the GB virus C/hepatitis G virus"
M. Fogeda, S. Navas, J. Martín-García, M. Casqueiro, E. Rodríguez, C. Arocena, and V. Carreño
Journal of Virology, 73: 4052-4061, 1999
"Genetic diversity and tissue compartmentalization of the hepatitis C virus genome in blood mononuclear cells, liver, and serum from chronic hepatitis C patients"
S. Navas, J. Martín-García, J.A. Quiroga, I. Castillo, and V. Carreño
Journal of Virology, 72: 1640-1646, 1998