Julio Martín-García Assistant Professor, Microbiology and Immunology Ph.D., 1997, Universidad Autónoma de Madrid, Spain 245 N. 15th Street Mail Stop 1013A, Room 18307 Philadelphia, PA 19102 Office: 215-762-7586 Lab: 215-762-1479 Email: julio.martin-garcia@drexelmed.edu

Research Staff: Manideepthi Nimmagadda, Fiorella Rossi
Undergraduate Students: Bianca Querido (Undergraduate Internship Program, School of Sciences, Utrecht University, The Netherlands)

Keywords:

Human immunodeficiency virus, envelope glycoproteins, viral fusion and entry, CD4, chemokine receptors, receptor interaction, central nervous system, macrophages and microglia, cellular activation, viral neuropathogenesis

Research Interests:

HIV-1 enters the central nervous system (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.

Using an in vitro microglia-adapted HIV-1 isolate, which was obtained by sequential passages in pure human adult microglial cultures to mimic the potential adaptation of primary, peripheral HIV-1 isolates to replication in microglial cells in the brain, we showed that viruses with envelopes of lower CD4-dependence, reduced glycosylation and partially-triggered conformation, but more sensitive to neutralization by antibodies, may arise in the CNS due to the adaptation to microglial cells, resulting in a more stable interaction with CD4 and the increase in fitness for the target cell population in this specific niche. In collaboration with Dr. Irwin Chaiken’s laboratory (Biochemistry Dept.), we also found that the monomeric gp120 of the microglia-adapted virus had increased affinity for CD4 and antibodies to CD4-induced epitopes, and this correlated with decreased sensitivity to neutralization by anti-CD4 antibodies in the context of viral particles (surrogate for CD4:trimeric envelope interaction).

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 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.

Finally, since the neurotropism of HIV-1 has been almost exclusively studied to date with isolates belonging to subtype B (the most prevalent in US and Western Europe), we are expanding our research to other viral subtypes, 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.

Schematic depiction of HIV neuroinvasion and syncytia formation(González-Scarano and Martín-García, Nature Reviews Immunology 2005; 5:69-81).

Selected Publications:

1. Navas S, Martín J, Quiroga JA, Castillo I, Carreño V. Genetic diversity and tissue compartmentalization of the hepatitis C virus genome in blood mononuclear cells, liver, and serum from chronic hepatitis C patients. Journal of Virology 1998; 72: 1640-1646.
   
   
2. Martín J, Navas S, Quiroga JA, Colucci G, Pardo M, Carreño V. Quantitation of hepatitis C virus (HCV) RNA in liver and peripheral blood mononuclear cells from patients with chronic HCV infection. Journal of Medical Virology 1998; 54: 265-270.
   
   
3. Martín J, Navas S, Quiroga JA, Pardo M, Carreño V. Effects of the ribavirin-interferon a combination on cultured peripheral blood mononuclear cells from chronic hepatitis C patients. Cytokine 1998; 10: 635-644.
   
   
4. Fogeda M, Navas S, Martín J, Casqueiro M, Rodríguez E, Arocena C, Carreño V. In vitro infection of human peripheral blood mononuclear cells by the GB virus C/hepatitis G virus. Journal of Virology 1999; 73: 4052-4061.
   
   
5. Martín J, Navas S, Fernández M, Rico M, Pardo M, Quiroga JA, Zahm F, Carreño V. Antiviral effect of amantadine and interferon α-2a against hepatitis C virus on peripheral blood mononuclear cells from chronic hepatitis C patients. Antiviral Research 1999; 42: 59-70.
   
   
6. Shieh JTC, Martín J, Baltuch G, Malim MH, González-Scarano F. Determinants of syncytium formation in microglia by human immunodeficiency virus type 1: role of the V1/V2 domains. Journal of Virology 2000; 74: 693-701.
   
   
7. Albright AV, Martín J, O’Connor M, González-Scarano F. Interactions between HIV-1 gp120, chemokines, and cultured adult microglial cells. Journal of Neurovirology 2001; 7: 196-207.
   
   
8. Martín J, LaBranche CC, González-Scarano F. Differential CD4/CCR5 utilization, gp120 conformation, and neutralization sensitivity between envelopes from a microglia-adapted human immunodeficiency virus type 1 and its parental isolate. Journal of Virology 2001; 75: 3568-3580.
   
   
9. Martín-García J, Kolson DL, González-Scarano F. Chemokine receptors in the brain: their role in HIV infection and pathogenesis. AIDS 2002; 16: 1709-1730.
   
   
10. González-Scarano F, Martín-García J. The neuropathogenesis of AIDS. Nature Reviews Immunology 2005; 5: 69-81.
    
    
11. Martín-García J, González-Scarano F. Viral receptors and the mechanisms of HIV-1 entry into cells and the central nervous system. In Gendelman H, et al. eds., “The Neurology of AIDS, 2nd Ed.”, pp. 125-146. Oxford University Press, London, 2005.
    
    
12. Martín-García J, Cocklin S, Chaiken IM, González-Scarano F. Interaction with CD4 and antibodies to CD4-induced epitopes of the envelope gp120 from a microglia-adapted human immunodeficiency virus type 1 isolate. Journal of Virology 2005, 79: 6703-6713.
    
    
13. Chen MF, Westmoreland S, Ryzhova EV, Martín-García J, Soldan SS, Lackner A, González-Scarano F. Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology. Journal of Neurovirology 2006; 12:73-89.
    
    
14. Martín-García J, Cao W, Varela-Rohena A, Plassmeyer ML, González-Scarano F. HIV-1 tropism for the central nervous system: brain-derived envelope glycoproteins with lower CD4-dependence and reduced sensitivity to a fusion inhibitor. Virology 2006; 346:169-179.
    
    
15. Cocklin S, Gopi H, Querido B, Nimmagadda M, Kuriakose S, Cicala C, Ajith S, Baxter S, Arthos J, Martín-García J, Chaiken IM. Broad-spectrum anti-HIV potential of a peptide HIV-1 entry inhibitor. Journal of Virology 2007; 81:3645-3648.