AEGiS-12IAC: Actin dependent dual receptor HIV-1 infection vs. single receptor chemotaxis induction by HIV-1 envelope.

12th International AIDS Conference

Geneva, Switzerland - June 28-July 3, 1998

Actin dependent dual receptor HIV-1 infection vs. single receptor chemotaxis induction by HIV-1 envelope.

Int Conf AIDS 1998 Jun 28-Jul 3; 12:6 (abstract no. 11120)

Schwartz DH, Iyengar S, Hildreth JE, Mitchell JB
MMI, Johns Hopkins School Public Health, Baltimore, MD, USA.

BACKGROUND: CD4 independent cultured HIV isolates have been described. Given the mutability of HIV-1 envelope, why do almost all isolates retain a requirement for dual receptor binding? Do similar requirements apply to gp120 induced chemotaxis?

OBJECTIVES: To understand envelope-receptor interactions of HIV infection and HIV induced chemotaxis. METHODS AND

RESULTS: Peripheral blood mononuclear cells (PBMCs) were activated with PHA and exposed to 100 TCID50 HIV-1MN. Transient 1 hr pretreatment with 1 microM Cytochalasin D (CyD), which disrupts cytoskeletal actin filament attachment to transmembrane proteins, blocked infection at the entry step. This was demonstrated by decreased p24 internalization@1 hr, reverse transcribed DNA@8 hrs, and virus production@day 7. Cell division and viral budding were unaffected by CyD at this dose. Confocal fluorescent microscopy of PHA stimulated PBMCs revealed polarized co-capping of CD4 and CXCR4 (60O) and pseudopod formation (90') induced by MN rgp120. These membrane changes were blocked by pretreatment with CyD. Staining with B4 mAb (UBI, Inc.) specific for a conformational epitope dependent on CD4-chemokine receptor (CKR) heterodimerization demonstrated equal or greater expression after Cy D treatment. In contrast, chemotaxis induced by HIV-1MN or MN rgp120 was CD4 independent, requiring only gp120-CXCR4 binding. Native, heat denatured, and reduced carboxymethylated gp120 were all chemotactic for both CD4+ or CD8+ lymphocytes. Chemotaxis was blocked by mAb to CXCR4 but not by mAb to CD4 which prevented gp120-CD4 binding.

CONCLUSIONS: Beyond heterodimerization, the requirement of actin dependent CD4-CKR cocapping for HIV entry may ensure that virions do not enter cells in early apoptosis (which lose the ability to form cytoskeletal actin filaments). Movement of cells along a gradient of gp120 also requires intact actin, but only gp120 engagement of fusin. The selective value to HIV of attracting CD4 negative cells is unclear, but CD8+ T cell migration to germinal centers is thought to be important in pathogenesis.

Keywords: AEGIS, HIV-1, Receptors, CXCR4, Antigens, CD4, HIV Infections, Actins, CD4-Positive T-Lymphocytes, Single Person, Carrier Proteins, CD8-Positive T-Lymphocytes, Virion, T-Lymphocytes, Antibodies, Monoclonal, Greece, immunology, ICA12
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