News and Publications

Viral and Host Factors in HIV-1 Infection

D.E. Mosier, A. Beernink, J.M. Glynn, R.J. Gulizia, Y. Lin, D. McElligott, D. McKinney, C. Pastore, P. Poignard, G. Picchio, B. Sabbe, S. Venturini, M. McGrath,* B. Herndier,* B. Chesebro**

* University of California, San Francisco, CA
** Rocky Mountain Laboratories, Hamilton, MT

Infection of humans with HIV type 1 (HIV-1) leads to progressive depletion of CD4 T cells until AIDS develops. HIV-1 isolates differ extensively in their target cells and in their ability to kill infected cells. We are studying how different HIV-1 isolates cause disease in a unique small animal model of HIV-1 infection. In this model, human peripheral blood leukocytes (PBLs) transplanted to mice with severe combined immunodeficiency (SCID) survive to generate hu-PBL-SCID mice. We are using a variety of strategies to treat or prevent HIV-1 infection in this model.

The cell targets for HIV-1 infection are defined by their expression of the cell receptors used for viral entry. The HIV envelope glycoprotein (gp120) binds to CD4 and to one of several chemokine receptors to initiate infection. Primary infection of humans usually involves transmission of macrophage-tropic, non--syncytial-inducing viruses that use the chemokine CCR5 as the coreceptor for viral entry. The HIV-1 gp120 sequence evolves in about 50% of infected persons to allow use of the chemokine CXCR4 as a coreceptor for entry, a change that is associated with more rapid progression of HIV disease. HIV-1 nomenclature recently changed to indicate use of coreceptors: R5 viruses use CCR5, X4 viruses use CXCR4, and R5X4 viruses use either CCR5 or CXCR4.

The reasons for the more efficient transmission of R5 viruses and the slow evolution of X4 variants remain unclear. We recently showed that plasma levels of viral RNA and the extent of depletion of CD4⁺ T cells in hu-PBL-SCID mice differ after infection with R5, R5X4, or X4 HIV-1 isolates, including isolates with minimal sequence difference in the V3 region of gp120. R5 viruses produced sustained infection. R5X4 and X4 isolates caused more rapid depletion of CD4⁺ T cells than did R5 viruses, and the duration of infection was shorter.

We examined the target-cell limitations on viral spread by analyzing CCR5 and CXCR4 expression on the human cells engrafted in hu-PBL-SCID mice. The CCR5 coreceptor is expressed primarily on memory T cells, whereas the CXCR4 coreceptor is expressed on both naive and memory T cells. We found that CCR5 expression was limited to about 30% of CD4⁺ T cells in lymph nodes and that R5 viruses established persistent infection at this site. CXCR4 was expressed on about 90% of CD4⁺ T cells. The switch from use of CCR5 to use of CXCR4 thus broadens the target-cell range 3-fold, a change that accelerates the loss of CD4⁺ T cells.

HIV-1 infection of hu-PBL-SCID mice continues to be a valuable model for testing vaccine approaches to preventing transmission of HIV. Both neutralizing antibodies and cytotoxic T lymphocytes can prevent infection. We recently examined whether these antibodies and cells can have a marked impact on established infection.

Administration of high concentrations of 1--3 potent neutralizing antibodies to mice with persistent infection resulted in a transient decrease in viremia and the rapid appearance of neutralization-resistant mutants. When cytotoxic T lymphocytes specific for the HIV gag-encoded protein p17 derived from a monozygotic twin infected with HIV were passively transferred to hu-PBL-SCID mice derived by using PBLs from the uninfected twin, a substantial, immediate decline in viremia occurred that persisted for 1 week or more. However, virus was not eradicated by therapy with cytotoxic T lymphocytes, because injection of new, activated CD4⁺ target cells led to the rescue of virus.

Antagonists of CCR5 have been relatively effective in reducing viral replication in hu-PBL-SCID mice, although eradication of virus has been difficult. Agents that target the cell receptors for virus rather than the viral envelope itself have not led to the generation of escape mutants. These observations suggest that multiple strategies will be necessary in immune-based therapies for established infection and that development of effective preventive vaccines still faces many obstacles. Once viral infection is established, the rapid mutation rate of HIV-1 provides the virus with many opportunities to evade immune control.

PUBLICATIONS

Picchio, G.R., Gulizia, R.J., Mosier, D.E. Chemokine receptor CCR5 genotype influences the kinetics of human immunodeficiency virus type 1 infection in human PBL-SCID mice. J. Virol. 71:7124, 1997.

Picchio, G.R., Gulizia, R.J., Wehrly, K., Chesebro, B., Mosier, D.E. The cell tropism of human immunodeficiency virus type 1 determines the kinetics of plasma viremia in SCID mice reconstituted with human peripheral blood leukocytes. J. Virol. 72:2002, 1998.

Picchio, G.R., Sabbe, R.E., Gulizia, R.J., McGrath, M., Herndier, B.G., Mosier, D.E. The KSHV/HHV8-infected BCBL-1 lymphoma line causes tumors in SCID mice but fails to transmit virus to a human peripheral blood mononuclear cell graft. Virology 238:22, 1997.

Scheuring, U.J., Corbeil, J., Mosier, D.E., Theofilopoulos, A.N. Early modification of host cell gene expression induced by HIV-1. AIDS 12:563, 1998.