␥␦ T cells are primarily found in the gastrointestinal mucosa and play an important role in the first line of defense against viral, bacterial, and fungal pathogens. We sought to examine the impact of human immunodeficiency virus type 1 (HIV-1) infection on mucosal as well as peripheral blood ␥␦ T-cell populations. Our results demonstrate that HIV-1 infection is associated with significant expansion of V␦1 and contraction of V␦2 cell populations in both the mucosa and peripheral blood. Such changes were observed during acute HIV-1 infection and persisted throughout the chronic phase, without apparent reversion after treatment with highly active antiretroviral therapy (HAART). Despite an increase in the expression of CCR9 and CD103 mucosal homing receptors on peripheral blood ␥␦ T cells in infected individuals, mucosal and peripheral blood ␥␦ T cells appeared to be distinct populations, as reflected by distinct CDR3 length polymorphisms and sequences in the two compartments. Although the underlying mechanism responsible for triggering the expansion of V␦1 ␥␦ T cells remains unknown, HIV-1 infection appears to have a dramatic impact on ␥␦ T cells, which could have important implications for HIV-1 pathogenesis.␥␦ T cells are minor constituents in the peripheral blood but provide a sizable contribution to the immune compartment of the gastrointestinal mucosa, likely representing the first defense against pathogens crossing this surface. In the mucosa, they constitute up to 50% of all lymphocytes in the intraepithelial compartment and approximately 10% of lymphocytes in the lamina propria (26, 44). Mucosal ␥␦ T cells are ideally situated to contribute to the earliest stages of the immune response against infection through epithelial surfaces and are believed to link the innate and acquired immune responses. In addition, ␥␦ T cells influence gastrointestinal epithelial cell proliferation and differentiation (27) and development of mucosal immunoglobulin A-producing B cells and play a role in oral tolerance (15).␥␦ T cells recognize soluble protein and nonprotein antigens, though the mechanism by which these antigens are recognized remains enigmatic. Unlike ␣␤ T cells, ␥␦ T cells recognize antigens via their T-cell receptor (TCR) in a major histocompatibility complex (MHC)-independent manner. The ␥␦ TCR recognizes intact proteins in a fashion similar to that in which antibodies recognize antigens. ␥␦ T cells employ a distinct set of variable (V), diversity (D), and joining (J) regions. Though the potential of ␥␦ TCR diversity is, in theory, greater than that of ␣␤ T cells (7), reduced combinatorial somatic recombination results in restricted ␥␦ TCR diversity. Despite a restriction in receptor diversity, the lack of antigenic processing or MHC restriction permits recognition of a wide variety of native and foreign antigens. Though there are six known ␥ and six known ␦ chains, peripheral blood ␥␦ T cells in healthy individuals predominantly express the V␦2 and V␥9 TCR variable segments (8).The physiologic role of ␥␦ T ce...

Sixteen subjects were treated with highly active antiretroviral therapy within 120 days of the onset of symptoms of newly acquired human immunodeficiency virus type 1 (HIV-1) infection. Eleven of the 16 participated in an adjunctive therapeutic vaccine trial. After a mean of 3.2 years of treatment, they elected to discontinue therapy. Virus rebound occurred in all subjects and was followed by a spontaneous, transient although significant reduction in log plasma HIV-1 RNA level, ranging from 0.3 to 3.1 log(10) copies/mL. Despite evidence of the induction of HIV-1-specific cell-mediated immune responses, plasma viremia was not persistently suppressed to <500 copies/mL in any subject. The magnitude and dynamics of virus rebound were similar in both vaccinated and unvaccinated subjects. Nevertheless, given the transient suppression of viremia observed in nearly all subjects after treatment has been discontinued, further investigations of adjunctive vaccination with optimized antiretroviral therapy in treating HIV-1 infection are warranted.

In order to boost immune responses in persons in whom highly active antiretroviral therapy (HAART) was initiated within 120 days of the onset of symptoms of newly acquired human immunodeficiency virus type 1 (HIV-1) infection, we administered vaccines containing a canarypox virus vector, vCP1452, with HIV-1 genes encoding multiple HIV-1 proteins, and recombinant gp160. Fifteen HIV-1-infected subjects who achieved sustained suppression of plasma viremia for at least 2 years were enrolled. While continuing antiretroviral therapy, each subject received at least four intramuscular injections of the vaccines on days 0, 30, 90, and 180. Adverse events were mild, with the most common being transient tenderness at the vCP1452 injection site. Of the 14 patients who completed vaccination, 13 had significant increases in anti-gp120 or anti-p24 antibody titers, and 9 had transient augmentation of their T-cell proliferation responses to gp160 and/or p24. HIV-1-specific CD8؉ T cells were quantified using an intracellular gamma interferon staining assay. Among 11 patients who had increased CD8 ؉ T-cell responses, seven had responses to more than one HIV-1 antigen. In summary, vaccination with vCP1452 and recombinant gp160 appears safe and immunogenic in newly HIV-1-infected patients on HAART.