International AIDS Society–USA Topics in HIV Medicine HIV Pathogenesis and Vaccine Development Amitinder Kaur, MD, and R. Paul Johnson, MD Continuing the trend of recent years, long-term nonprogression (LTNP) with HIV-specific CD8+ T cells was 5705 the 10th Conference on Retroviruses strong HIV-specific CD4+ and CD8+ T- spot-forming cells/106 peripheral blood and Opportunistic Infections offered a cell responses is well-established, the mononuclear cells (PBMCs) (range, 185- strong and diverse array of presenta- factors associated with progressive HIV 25,000). Although the plasma HIV-1 tions on AIDS pathogenesis and vaccine infection are not well-understood. RNA levels and CD4+ T-cell counts in development. Recent advances in Using a panel of 410 overlapping this group showed a weak inverse cor- pathogenesis research highlighted peptides spanning all HIV proteins of a relation with the breadth and magni- efforts to understand how HIV persists clade B consensus sequence, Kaufmann tude of the CD8+ T-cell response, a in the face of a vigorous immune and Draenert presented results of a striking overlap in the magnitude and response and underscored the impor- comprehensive investigation of the total breadth of CD8+ T-cell responses was tance of assessing functional properties HIV-specific CD4+ and CD8+ T-lym- observed between progressors and of cellular immune responses. This phocyte response in different cohorts LTNPs. Thus, in 25 LTNPs, recognition of year's conference also witnessed a of HIV-infected subjects. Kaufmann a median of 16 peptides (range, 5-58) resurgence of interest in neutralizing (Abstract 31) presented an analysis of with magnitudes ranging between 1046 antibody responses, and numerous HIV-specific CD4+ T-cell responses in and 43,000 spot-forming cells/106 efforts to translate new insights into the 32 HIV-infected subjects who either PBMCs (median, 7980) did not differ structure of the HIV-1 envelope and were on highly active antiretroviral ther- significantly from progressors. neutralizing antibodies to the develop- apy (HAART) or were off therapy and Since T-lymphocyte responses to HIV ment of new vaccine approaches able to had relatively low plasma HIV-1 RNA have been routinely measured using induce broadly neutralizing antibodies. levels (median, 2850 copies/mL). HIV- nonautologous viral sequences, the real Nonhuman primate vaccine studies specific CD4+ responses were focused breadth and magnitude of the HIV-spe- offered encouraging results of novel on relatively few epitopes, predomi- cific T-cell response as gauged by autol- approaches able to induce protection nantly found in Gag and Nef. CD4+ T- ogous virus sequences is likely to be against pathogenic simian immunodefi- cell responses to at least 1 HIV peptide even greater. Using peptide sets from a ciency virus (SIV) isolates but also were detected in 78% of patients, and a clade B consensus sequence, Altfeld and offered concerning caveats regarding median of 4.5 peptides were recognized colleagues (Abstract 314) showed that the potential for viral escape and the by each subject. Despite the presence of the virus-specific T-cell response clus- impact of host genotype on vaccine pro- disparate human leukocyte antigen tered in conserved regions of the tection. (HLA) class II alleles, 7 peptides (5 in genome. However, when responses to Gag and 2 in Nef) were recognized by peptides spanning the consensus and Immune Control of HIV: Size is 75% of the subjects, including 1 that autologous virus sequences of Tat, Vpr, Not Enough was recognized in 56% of subjects. This and p24-Gag were compared, the autol- finding suggests a relatively promiscu- ogous sequences demonstrated broader In the ongoing quest for an effective ous presentation of CD4+ T-cell epi- and significantly stronger responses, AIDS vaccine, advancing our under- topes by different HLA class II alleles. In particularly those directed against the standing of the barriers that impede contrast to the CD4+ T-cell response, variable regulatory proteins. Thus, dif- immune control of viral replication in the CD8+ T-cell response in this cohort ferences between controllers and non- HIV-infected individuals is of paramount of HIV-infected subjects was 10-fold controllers of HIV infection may be bet- importance. Although the association of greater in magnitude and broadly ter appreciated using autologous virus directed, targeting reverse transcriptase sequences. However, Migueles (Abstract Dr Kaur is Instructor in Medicine at (RT), integrase, and Env in addition to 318) showed that the frequency of the Division of Immunology, New Gag and Nef. A similar pattern of vigor- CD8+ T lymphocytes secreting interfer- England Regional Primate Center, ous and broad HIV-specific CD8+ T-cell on-γ in response to stimulation with Harvard Medical School, in South- responses was also observed by autologous virus-infected CD4+ T cells borough, Mass. Dr Johnson is Associate Draenert (Abstract 35) in 26 chronically was equivalent in LTNPs and progres- Professor of Medicine at the Division HIV-infected subjects with late-stage sors. In addition, variant peptides with of Immunology, New England HIV infection (mean plasma HIV-1 RNA autologous virus sequences were well- Regional Primate Center, and at the level, 186,271 copies/mL, and mean recognized, demonstrating that loss of Infectious Disease Unit and Partners CD4+ count, 141 cells/µl). A median of immune control can occur in the pres- AIDS Research Center, Massachusetts 13.5 peptides (range, 2-39) were recog- ence of persistent recognition of autolo- General Hospital, Harvard Medical nized by individual progressors in this gous virus sequences. School, in Charlestown, Mass. group, and the median magnitude of These data highlight the paradox 76 Conference Highlights - HIV Pathogenesis and Vaccine Development Volume 11 Issue 3 May/June 2003 that despite the fact that HIV infection is represent novel CD8+ T-cell epitopes in marked inability to proliferate in highly immunogenic, induction of a the autologous virus or sites of escape response to antigen-specific stimulation strong and broad anti-HIV response is from CD4+ T lymphocytes or anti- in progressors but not in LTNPs. This not in itself sufficient for effective bodies. defect in proliferative capacity was immune control. This finding raises the Loss of immune control in the set- linked to a lack of perforin expression in possibility that factors other than the ting of a strong and broad HIV-specific the nonproliferating antigen-specific overall magnitude of cellular immune T-lymphocyte response was also CD8+ T cells. A similar defect in prolif- responses may be critical in the ability observed in subjects undergoing struc- erative capacity has been seen in HIV- of the host to control HIV infection. Are tured treatment interruptions (STIs) fol- specific CD4+ T cells in individuals on there distinct functional properties of lowing institution of HAART in acute STI during viremic episodes. the HIV-specific T-cell response associat- HIV infection. Walker presented an Price and colleagues (Abstract 32) ed with an effective immune response? update on 14 such subjects. Substantial compared the physical enumeration of Presentations by Walker (Abstract 164) augmentation of cellular immunity was HIV-specific CD8+ T lymphocytes by and Connors (Abstract 165) addressed observed following each episode of STI. tetramers or by clonotypic quantitative this key issue. In 1 individual, the number of peptides polymerase chain reaction for the T-cell The ability of cytotoxic T lympho- recognized increased from 2 pre-STI to receptor B (TCRB) locus of defined HIV- cytes (CTLs) to control HIV replication 25 at the end of the second STI. Post-STI specific CTL clones with functional enu- may be dependent on a variety of fac- responses were also broader, encom- meration of interferon-γ producing cells tors, including genetic background, passing both structural and regulatory during viremic and aviremic episodes in presence of CTL escape, and defects in proteins. Although the pre-STI respons- 133 HIV-infected subjects enrolled in CTL maturation or function. In his pre- es were exclusively in Gag, Env, or Nef, the Swiss HIV Cohort Study. In this sentation, Walker (Abstract 164) pro- following STI, 100% of the responses study, individuals were subjected to posed that one of the reasons underly- targeted Nef, Env, and Pol; 88% target- cycles of 8 weeks on and 2 weeks off ing lack of effective viral control with ed Gag; and 38% to 60% were directed therapy, and treatment was discontin- strong CTL responses may be related to toward regulatory proteins. However, ued after 4 such cycles. During “off- epitope-specific or allele-specific quali- even this augmentation in breadth was treatment” phases, increases in plasma tative differences among CTLs. These not sufficient to sustain inhibition of HIV-1 RNA levels were associated with variations may lead to differences in the viral replication, and eventually decline in interferon-γ ELISPOT respons- propensity for and the consequences of immune control was lost. No benefit in es in the presence of stable or increased CTL escape. Thus, loss of certain CTL survival was observed in an intent-to- frequencies of tetramer-positive cells. In responses may be more important than treat analysis. However, there was some contrast, the frequency of tetramer-pos- loss of others. One such example is the benefit in terms of plasma HIV-1 RNA itive and interferon-γ-positive cells consequence of CTL escape in a single levels, in that the time to reach greater approximated each other in aviremic B27-restricted epitope (KK10). Although than 30,000 HIV-1 RNA copies/mL in individuals. Functional and nonfunc- the presence of HLA-B27 is highly asso- plasma was slowed in individuals on tional CD8+ T cells had the same clon- ciated with nonprogression in HIV- STIs. ality and were not preferentially infect- infected individuals, escape in this par- What qualitative defects are corre- ed with HIV.