View All Abstracts for Session 66
LB3 Dynamics of HIV-1 Immune Control and Escape
G. Shaw*1, X. Wei1, N. Jones2, M. Saag3, B. Korber4, M. Nowak5, and P. Borrow2
1Howard Hughes Med. Inst., Birmingham, AL, USA; 2Edward Jenner Inst. for Vaccine Res., Compton, UK; 3Univ. of Alabama at Birmingham, USA; 4Los Alamos Natl. Labs, NM, USA; and 5IAS, Princeton, NJ, USA
Background: Previously, we analyzed the kinetics of HIV-1 elimination and appearance of drug resistant mutants to infer the extraordinary dynamics of virus turnover and the surprisingly brief lifespan of productively infected lymphocytes in vivo. We have now taken a similar approach to evaluate the magnitude and kinetics of CTL activity in controlling HIV-1 replication in acute and
established infection.
Methods: Three patients with acute infection were identified prior to seroconversion and studied intensively by coordinated immunological and viral genetic analyses over 3 years.
Results: Autologous CTL recognition was detected by cell killing and ELISPOT assays to 8 epitopes in gp160, gag, and tat in patient 1; to 9 epitopes in the same proteins in patient 2; and to 29 epitopes in gp160, gag, tat, pol, and nef in patient 3. Total plasma vRNA corresponding to each genomic region was sequenced over time, along with 1,089 subgenomic plasma-derived viral cDNA clones and 45 full-length gp160 clones. In patients 1 and 2, the breadth of the earliest CTL response was narrow, complete CTL escape occurred within weeks at several epitopes, and subsequent plasma virus set points were high. Conversely, in patient 3, the breadth of the earliest CTL response was wide, CTL escape did not occur at any of 28 epitopes, and the subsequent plasma viral setpoint was low. Patient 1 was infected by 2 divergent strains of HIV-1, and multiple viral recombination events were found to contribute to viral persistence.
Conclusions: The magnitude (>95%) and kinetics (weeks) of replacement of wild-type plasma virus by CTL escape mutants is comparable to that elicited by antiretroviral drugs and indicates a strong, biologically significant CTL activity in HIV-1 infection. Ironically, only modest (yet variable) decrements in the lifespan of productively infected cells resulting from CTL killing may be responsible for this effect as well as for clinically important differences in plasma viral set points between patients. Candidate vaccines should strive for breadth of CTL response.
Contact Author about this Abstract
