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BackgroundHLA class I contributes to HIV immune control through antigen presentation to cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In contrast to investigations of CTL, studies of NK cells in HIV control through HLA-killer immunoglobulin-like receptor (KIR) interactions remain sparse in African cohorts.MethodsTreatment-naive, chronically HIV-infected adults (N = 312) were recruited from South Africa, and the effects of HLA-KIR pairs on clinical outcome were analyzed.ResultsThere was no significant difference in viral load among all subjects with HLA alleles from the HLA-C1 group (P = .1). However, differences in HLA-C type significantly influenced viremia among 247 KIR2DL3 positives (P = .04), suggesting that specific HLA-KIR interactions contribute to immune control. Higher viral load (P = .02) and lower CD4+ T-cell counts (P = .008) were observed in subjects with HLA-C*16:01+KIR2DL3+. Longitudinal analysis showed more rapid progression to AIDS among HLA-C*16:01+KIR2DL3+ subjects (adjusted hazard ratio 1.9, P = .03) than those without this genotype, independent of CD4+ T-cell count and viral load.ConclusionsThese results highlight the existence of unique anti-HIV innate immunity within distinct populations and the contribution of KIR on NK cells and some CTLs to the well-described HLA-mediated impact on HIV disease progression.

Background. Human immunodeficiency virus type 1 (HIV-1)–specific CD8+ responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8+ T-cell epitopes during and after acute viremia are lacking. Methods. We characterized CD8+ T-cell responses in 20 acutely infected, antiretroviral-naive individuals with HIV-1 subtype C infection using the interferon-γ enzyme-linked immunosorbent spot assay. Eleven of these had not fully seroconverted at the time of analysis. Viruses from plasma were sequenced within defined cytotoxic T-lymphocyte (CTL) cell epitopes for selected subjects. Results. At approximately 28 days after estimated initial infection, CD8+ T-cell responses were directed against an average of 3 of the 410 peptides tested (range, 0–6); 2 individuals had no detectable responses at this time. At 18 weeks, the average number of peptides targeted had increased to 5 (range 0–11). Of the 56 optimal Gag CTL epitopes sequenced, 31 were wild-type in the infecting viruses, but only 11 of 31 elicited measurable CD8+ T-cell responses. Conclusions. These data demonstrate that the majority of CD8+ responses are not elicited during acute HIV infection despite the presence of the cognate epitope in the infecting strain. There is a need to define factors that influence lack of induction of effective immune responses and the parameters that dictate immunodominance in acute infection.

A robust cell-mediated immune response is vital for the resolution of acute infection with human immunodeficiency virus type 1 (HIV-1) and long-term control of disease progression [1–5]. HIV-1 vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point [6], which may reduce infectivity and delay disease progression. AIDS Clinical Trials Group (ACTG) protocol A5197 was a randomized, placebo-controlled trial to test the effect of a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag therapeutic vaccine on plasma viral load (PVL) in participants undergoing an analytic treatment interruption (ATI) [7]. A total of 110 participants underwent a 16-week ATI after randomization in a 2:1 ratio to receive 3 doses of either vaccine or placebo. Although there was a trend toward a vaccine benefit, this difference failed to reach statistical significance for the prespecified coprimary ATI endpoints (PVL set point: mean of ATI week 12 and 16 PVL and time-averaged area under the curve). However, a secondary analysis based on PVL at ATI week 16 (w16 PVL) found that HIV-1 RNA levels were 0.5 log10 lower in the vaccine arm [7, 8]. The influence of HLA class I alleles on viral evolution, disease progression, and PVL is well known [9–14]. A number of “protective” alleles (HLA B*13, B*27, B*51, B*57, and B*5801) are associated with lower levels of viremia, delayed disease progression, and/or improved outcomes [10, 15–20]. “Unfavorable” HLA alleles associated with accelerated disease progression include the HLA-B*35-Px variants (B*3502, 3503, 3504, or 5301) [21, 22]. In this analysis, we describe the distribution of HLA alleles in ACTG A5197 and explore their impact on the w16 PVL response to a rAd5 HIV-1 gag vaccine. This vaccine induced significant CD4+ and CD8+ HIV-specific T cell responses [7]. In addition to HLA and T cell activation, other factors that may play a role in vaccine effectiveness and viral rebound include pre-antiretroviral therapy (ART) PVLs [23–25], CD4+ T cell counts [23, 24], HLA-associated viral polymorphisms [14], preexisting Ad5 antibody titers [26], and sequence similarity of patient virus to the vaccine [27]. Using a hypothesis-driven approach, we created a multiple linear regression model to identify factors independently correlated with virologic rebound. Because the more robust vaccine effect was not noted until ATI week 16, we focused our analysis on the w16 PVL outcome.

CD4+ T cells play a pivotal role in adaptive immunity, because they are required for the development and maintenance of memory and cytotoxic CD8+ T cells [1–4]. On the other hand, human immunodeficiency virus (HIV)–specific CD4+ T cells serve as the primary target cell population for viral replication [5]. Thus, induction of HIV-specific CD4+ T cells may have pleiotropic effects, on the one hand protecting against HIV through its role in adaptive immune responses but, at the same time, generating a pool of target cells for HIV propagation. HLA class II molecules are involved in presenting antigen to CD4+ T cells, and their role is therefore considered central for the development and maintenance of HIV-specific CD4+ T-helper cells. Of the 10 genes that encode for HLA class II molecules (reported as of January 2010), the DRB1 gene at the DRB locus is the most diverse, encoding for 762 distinct alleles (http://hla.alleles.org/nomenclature/stats.html). Despite the potential role of HLA class II alleles in HIV infection, only a limited number of alleles have been associated with HIV disease outcome [6–12]. In particular, several DRB1*13 alleles and the DRB1*13-DQB1*06 haplotype have been reported to confer a certain degree of protection, but all of these reports focused on highly selected patient subsets, including long-term nonprogressors, subjects treated during acute infection, and children with vertically transmitted HIV. The role of HLA class II alleles in chronic progressive HIV infection remains unknown. To investigate the effect of HLA class II alleles on disease progression in chronic HIV infection, we studied a well-characterized cohort of 426 antiretroviral therapy (ART)–naive, HIV-1 clade C–infected, mainly female black South Africans, as well as 1436 HIV-1 clade B virus–infected persons from the Multicenter AIDS Cohort Study (MACS). Here we report that the DRB1*1303 allele is associated with reduced viral loads (VLs) in both B and C clade populations, although DRB1*1303 expression was not associated with an increased frequency of interferon (IFN) γ–positive HIV-specific CD4+ T cell responses. This suggests that the protective activity of specific HLA class II alleles may be mediated via an alternative mechanism.

We have characterized an assay measuring CD8 T cell-mediated inhibition of human immunodeficiency virus (HIV) type 1 replication, demonstrating specificity and reproducibility and employing a panel of primary HIV-1 isolates. The assay uses relatively simple autologous cell culture and enzyme-linked immunosorbent assay, avoids generation of T cell clones, and can be performed with

Spontaneous control of human immunodeficiency virus (HIV) infection has been documented in a minority of HIV-infected individuals. The mechanisms behind this outcome remain largely unknown, and a better understanding of them will likely influence future vaccine strategies.HIV-specific T cell and antibody responses as well as host genetics were examined in untreated HIV-infected patients who maintain comparatively low plasma HIV RNA levels (hereafter, controllers), including those with levels of50 RNA copies/mL (elite controllers, n = 64), those with levels of 50-2000 copies/mL (viremic controllers, n = 60); we also examined HIV-specific T cell and antibody responses as well as host genetics for patients with levels of10,000 copies/mL (chronic progressors, n = 30).CD8+ T cells from both controller groups preferentially target Gag over other proteins in the context of diverse HLA class I alleles, whereas responses are more broadly distributed in persons with progressive infection. Elite controllers represent a distinct group of individuals who have significantly more CD4 and CD8 T cells that secrete interferon-gamma and interleukin-2 and lower levels of HIV-neutralizing antibodies. Individual responses were quite heterogeneous, and none of the parameters evaluated was uniquely associated with the ability to control viremia.Elite controllers are a distinct group, even when compared to persons with low level viremia, but they exhibit marked genetic and immunologic heterogeneity. Even low-level viremia among HIV controllers was associated with measurable T cell dysfunction, which has implications for current prophylactic vaccine strategies.

The escalating human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have had a significant impact on public health services in resource-limited settings. The province of KwaZulu-Natal in South Africa is estimated to have one of the greatest TB/HIV coinfection burdens on the African continent, coupled with historically low TB treatment success rates. In May 2004, the South African government began providing antiretroviral therapy (ART) for HIV-infected individuals within the public sector. As in many counties, this HIV treatment program was established in parallel with an existing TB treatment service. In 2005, the Integration of TB in Education and Care for HIV/AIDS (iTEACH) Program was launched in KwaZulu-Natal at Edendale Hospital. The goal of iTEACH was to identify barriers to effective treatment and develop support interventions to enable rapid expansion of access to ART and improve ART and TB treatment outcomes within the district served by this facility. In the present article, we discuss challenges to the delivery of TB and HIV care by these separate treatment programs, as well as opportunities to improve both TB treatment and ART outcomes through lessons learned during ART scale-up in the context of the HIV and TB coepidemics.

The immunological and virological impact of short-term treatment initiated during acute human immunodeficiency virus type 1 (HIV-1) infection was assessed prospectively in 20 subjects, 12 of whom initiated highly active antiretroviral therapy (HAART) for 24 weeks and then terminated treatment. Treatment resulted in suppression of viremia, an increase in the CD4 + T cell count, enhanced differentiation of HIV-1-specific CD8 + T cells from effector memory to effector cells at week 24 of HAART, and significantly higher virus-specific interferon-γ + CD8 + T cell responses after viral rebound (at week 48). However, despite these immunological changes, no differences in viremia or in the CD4 + T cell count were found 6 months after HAART was stopped, when treated subjects were compared with untreated subjects.

The evolution of Epstein-Barr virus (EBV)-specific T cell responses that occurs during the acute and persistent stages of infection remains poorly characterized despite its importance for developing immune interventions for EBV-associated disorders. This study assessed T cell responses to 113 EBV-derived epitopes in 40 subjects with acute or persistent EBV infection. Although no significant differences were seen in the breadth of CD8 and CD4 T cell responses, their magnitude differed significantly over time; acutely infected subjects generated especially strong responses to lytic viral antigens. The cross-sectional shift in immunodominance was also confirmed in subjects followed longitudinally from acute to persistent infection. In addition, human leukocyte antigen-matched siblings with discordant histories of symptomatic EBV infection showed no significant differences in their response patterns, suggesting that symptomatic EBV infection does not lead to unique persistent-stage responses. These data provide an assessment of immunodominance patterns and guidance for developing immunotherapeutic interventions for EBV-associated disorders.

Cellular immune responses to Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS and several other malignancies, are incompletely characterized. We assessed KSHV-specific interferon- gamma enzyme-linked immunospot responses in a cohort of 154 individuals, using overlapping peptide sets spanning the KSHV-encoded latency-associated nuclear antigen (ORF73) and the minor capsid glycoprotein (ORF65). Among KSHV-seropositive subjects, ORF73-specific responses dominated over responses to ORF65 and were preferentially detected in human immunodeficiency virus-coinfected individuals who had elevated levels of cell-associated KSHV DNA, indicating that the viral antigen burden may have been driving these responses. Responses to both ORF73 and ORF65 were also detected in several KSHV-seronegative subjects who were at increased risk for KSHV infection, which demonstrates that cellular immunity can be found in the absence of detectable humoral responses. These data have implications for the reliable identification of KSHV infection and may help guide the design of immune-based therapeutic and prophylactic interventions.

CC chemokine receptor 5 (CCR5) is a coreceptor for cellular entry of monocyte-tropic (R5) strains of human immunodeficiency virus (HIV) type 1, which has been implicated as the predominant phenotype of HIV in early infection. The CCR5 agonists macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normally T cell-expressed and -secreted) have been shown to block replication of R5 virus in vitro and have gained attention as potential antiviral factors. However, a few reports have suggested that other chemokines may also block R5 HIV-1, including monocyte chemoattractant protein (MCP)-2 (CC chemokine ligand 8). We demonstrate that MCP-2 specifically inhibits replication of R5 HIV-1 and that this activity is additive to that of RANTES. Furthermore, MCP-2 induces a robust, pertussis toxin-sensitive calcium flux in primary lymphocytes, and cross-desensitization studies indicate that MCP-2 acts via CCR5. These data confirm that MCP-2 is a ligand for CCR5 on CD4(+) lymphocytes and can specifically block R5 HIV-1.

The first prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine trial in Africa, with a clade B immunogen, is currently under way in Uganda, in a region where clades A and D are endemic. The use of a B clade vaccine is based on anticipated cross-recognition of endemic strains of HIV-1 in Uganda, but, in fact, little is known about the cytotoxic T lymphocyte (CTL) responses in that region. Seventeen HIV-1-infected volunteers from Kampala, Uganda, were studied to determine the immune responses elicited by natural infection with local HIV-1 strains. Despite the presence of broad cross-clade recognition, the CTL responses to the infecting viral clade were highest in most people. Recognition of nonendemic clade B antigens was similar to that of the coendemic local clade, and, in some instances, cross-recognition of clade B was greater. Nevertheless, the degree of cross-clade cellular responses we observed lends justification to the use of clade B-based immunogens in the current phase 1 vaccine trial in Uganda.

CD4 lymphocyte regenerative capacity was evaluated by use of an ex vivo outgrowth assay in human immunodeficiency virus (HIV)-1-infected subjects enrolled in a clinical trial (Merck 039). CD4 lymphocytes were selectively expanded in vitro by T cell receptor triggering, which also induces HIV production from latently infected cells. CD4 cell expansion and lack of virus production in cultures correlated well with clinical responses and were best in those receiving an aggressive antiretroviral three-drug regimen. Twelve clinical responders receiving triple-drug therapy monitored for 60 weeks had both excellent ex vivo CD4 cell expansion and lack of HIV replication, often in the absence of added drug in culture. Breakthrough viruses recovered from drug-containing arms of the cultures showed phenotypic resistance to the drugs used in vivo. This CD4 lymphocyte outgrowth assay correlates well with clinical outcome in subjects receiving potent antiretroviral regimens and may predict the emergence of early drug resistance.

The ARIEL Project for the Prevention of HIV Transmission from Mother to Infant was established to evaluate virologic and immunologic parameters during vertical transmission. To determine the strength and breadth of the cytotoxic T lymphocyte (CTL) response and its correlation with human immunodeficiency virus (HIV) transmission, a cross-sectional study was done of 31 HIV-infected pregnant women, of whom 15 transmitted and 16 did not transmit HIV to their infants. The precursor frequencies of CTL specific for HIV-1 gag, pol, nef, and env from 5 different isolates of the clade B of HIV-1 were determined by limiting dilution analysis. Results showed that variable levels of HIV-specific CTL response were present in HIV-infected pregnant women during and after pregnancy. In addition, CTL precursor frequencies specific for pol and nef were higher during pregnancy in nontransmitters than in transmitters. Thus, CTL responding to different HIV antigens may not be contributing equally to the prevention of vertical transmission.

Hepatitis C virus (HCV) is a common infection worldwide, and in most persons, it leads to persistent viremia and liver damage. Efforts to identify the correlates of protective immunity are hampered by this high rate of persistent infection in both infected humans and the only animal model, the chimpanzee. Peripheral blood mononuclear cells from seronegative persons were stimulated with synthetic peptides that represent epitopes recognized by HCV-specific cytotoxic T lymphocytes (CTL) after natural infection. In addition, CD4 + proliferative responses to recombinant HCV proteins were examined in these same persons. CTL responses directed against a peptide epitope of HCV and proliferative responses in 2 HCV-seronegative persons with possible occupational exposure to HCV were found. These otherwise healthy persons were not viremic, suggesting that they may have recovered from acute HCV infection. Characterization of virus-specific immune responses in exposed but seronegative persons may provide important clues as to the nature of protective immunity in HCV.

Background. Human immunodeficiency virus type 1 (HIV-1) elite controllers are able to control virus replication to levels below the limits of detection by commercial assays, but the actual level of viremia in these individuals is not well defined. Here, we quantify plasma HIV-1 RNA in elite controllers and correlate this with specific immunologic parameters. Methods. Plasma HIV-1 RNA levels were quantified in 90 elite controllers with use of a real time reverse-transcriptase polymerase chain reaction assay with a sensitivity of 0.2 copies/mL. HIV-1-specific immune responses and longitudinal CD4 + T cell counts were examined. Results. The median plasma HIV-1 RNA level was 2 copies/mL (interquartile range, 0.2-14 copies/mL). A longitudinal analysis of 31 elite controllers demonstrated 2-5-fold fluctuations in viremia in the majority of individuals; 6 had persistent levels below 1 copy/mL. Viremia correlated directly with HIV-1-specific neutralizing antibodies and Western blot reactivity but not with CD8 + T cell responses. Absolute CD4 + T cell decrease was more common among individuals with detectable viremia (P = .04). Conclusions. Low-level viremia is present in the majority of elite controllers and is associated with higher HIV-1-specific antibody responses. Absolute CD4 + T cell loss is more common among viremic individuals, suggesting that even very low-level viremia has negative consequences over time.

BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) epidemic is associated with a significant increase in the incidence of tuberculosis (TB); however, little is known about the quality of Mycobacterium tuberculosis (MTB)-specific cellular immune responses in coinfected individuals. METHODS: A total of 137 HIV-1-positive individuals in Durban, South Africa, were screened with the use of overlapping peptides spanning Ag85A, culture filtrate protein 10 (CFP-10), early secretory antigen target 6 (ESAT-6), and TB10.4, in an interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assay. Intracellular cytokine staining for MTB-specific production of IFN-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2 was performed, as was ex vivo phenotyping of memory markers on MTB-specific T cells. RESULTS: A total of 41% of subjects responded to ESAT-6 and/or CFP-10, indicating the presence of latent MTB infection. The proportion of MTB-specific IFN-gamma(+)/TNF-alpha(+) CD4(+) cells was significantly higher than the proportion of IFN-gamma(+)/IL-2(+) CD4(+) cells (P = .0220), and the proportion of MTB-specific IL-2-secreting CD4 cells was inversely correlated with the HIV-1 load (P = .0098). MTB-specific CD8 T cells were predominately IFN-gamma(+)/TNF-alpha(+)/IL-2(-). Ex vivo memory phenotyping of MTB-specific CD4 and CD8 T cells indicated an early to intermediate differentiated phenotype for the population of effector memory cells. CONCLUSIONS: Polyfunctional MTB-specific CD4 and CD8 T cell responses are maintained in the peripheral blood of HIV-1-positive individuals, in the absence of active disease, and the functional capacity of these responses is affected by HIV-1 disease status.

This supplement to the Journal of Infectious Diseases on tuberculosis (TB)/HIV coinfection came together as a result of a collaboration between the National Institutes of Health (NIH)-funded Centers for AIDS Research (CFARs) at Harvard University and at the University of Pennsylvania and the Forum for Collaborative HIV Research. It is based on 2 programs addressing TB/HIV coinfection research challenges. A steering committee consisting of Bruce Walker Edward Nardell Megan Murray and Eric Rubin (Harvard University); Gerald Friedland (Yale University); and James Hoxie (University of Pennsylvania); with the support of the national network of CFARs organized a symposium entitled "Confronting TB/HIV Co-infection" that was held on 30 June 2005 at Harvard University. The Forum for Collaborative HIV Research together with the International AIDS Society and the Agence National de Recherches sur le Sida et les Hepatites Virales with special support from Tibotec sponsored a special session entitled "HIV/TB: New Visions New Directions" during the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro on 25 July 2005 followed by a roundtable discussion with representatives from the World Health Organization HIV/ AIDS and Stop TB departments; the Global Fund to Fight AIDS Tuberculosis and Malaria; the NIH; the Centers for Disease Control and Prevention (CDC); and leaders from the pharmaceutical industry research networks and advocacy organizations. (excerpt)

Background. The relative immunogenicity of human immunodeficiency virus type 1 (HIV-1) proteins for CD8 + and CD4 + cell responses has not been defined. Methods. HIV-1-specific T cell responses were evaluated in 65 chronically HIV-1-infected untreated subjects by interferon-γ flow cytometry with peptides spanning the clade C consensus sequence. Results. The magnitude of HIV-1-specific CD8 + T cell responses correlated significantly with CD4' cell responses, but the percentage of CD8 + T cells directed against HIV-1 (median, 2.76%) was always greater than that of CD4 + cells (median, 0.24%). Although CD8 + T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4 + cell responses. There was no consistent relationship between virus-specific CD8 + or CD4' cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8 + T cell target was significantly lower than that in subjects in whom non-Gag proteins were the main target (P =.007). Conclusions. Gag-specific responses dominate the CD4 + T cell response to HIV, whereas CD8 + T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV-1. The preferential targeting of Gag by CD8 + T cells is associated with enhanced control of viral load.

Cytotoxic T lymphocytes (CTL) recognize and kill virus-infected cells and contribute to immunologic control of viral replication. For many herpesviruses (e.g., Epstein-Barr and cytomegalovirus), virus-specific CTL responses can be readily detected in infected persons, but CTL responses against Kaposi's sarcoma-associated herpesvirus (KSHV) appear to be weak and remain poorly characterized. Using a human leukocyte antigen (HLA) binding motif-based epitope prediction algorithm, we identified 37 HLA-A*0201 binding peptides from 8 KSHV open-reading frames (ORFs). After in vitro stimulation of peripheral blood mononuclear cells from KSHV-infected persons, CTL responses against 1 peptide in the KSHV kaposin protein (ORF K12) were detected in 2 HLA-A*0201-positive subjects. The optimal CTL epitope was identified by HLA restriction analysis and peptide titration assays. These data describe a latent phase viral gene product targeted by CTL that may be relevant for KSHV immunopathogenesis.

The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

Current treatments for human immunodeficiency virus (HIV) require uninterrupted drug administration because they are unable to reconstitute the immune response and do not affect the viral reservoir. Ten patients were treated during acute HIV infection before complete Western blot (WB) seroconversion with the combination of hydroxyurea, didanosine, and indinavir. This treatment was associated with the normalization of some immune parameters and functions. No loss of naive CD4 T lymphocytes was observed, and recovery of up to 35% of naive CD8 T lymphocytes occurred in several weeks. A vigorous HIV-specific T helper response (stimulation index 18) was observed in 7 of 8 patients treated before complete WB seroconversion but in only 1 of 5 controls treated after seroconversion. In addition, a limited latent viral reservoir (!0.02‐0.5 infectious units/10 6 cells) was documented in quiescent peripheral blood lymphocytes after treatment initiated before complete WB seroconversion. When treatment of human immunodeficiency virus (HIV) infection should be initiated remains an important unresolved question. Reasons to delay treatment include the likelihood of increased long-term toxicity, higher cost, and earlier development of drug resistance, thus narrowing the chances of later treatment options. Reasons to start treatment early are mainly theoretical and rely on the possibility that therapeutic intervention might limit damage to the immune system and confine the spread of HIV. The immune system is impaired by HIV infection. CD4 T

Expansion of CD4 lymphocytes from human immunodeficiency virus type 1 (HIV-1)-infected persons ex vivo has been limited by enhanced virus replication and cell death. The successful expansion of functional CD4 lymphocytes from HIV-1-infected persons has now been accomplished using a bispecific monoclonal antibody to CD3 and CD8 in combination with three antiretroviral agents. CD4 lymphocytes were polyclonally expanded by a factor of 10 3 -10 7 during 4-8 weeks in culture. Supernatants from most cultures were persistently HIV-1 p24 antigen-negative by day 14 and remained negative despite removal of antiretroviral agents at day 28. In such cultures, HIV-1 could not be recovered by cocultivation, and amounts of HIV-1 DNA declined or remained stable at low levels, eventually becoming undetectable in 2 cases. This approach establishes the feasibility of CD4 lymphocyte expansion in persons with HIV disease and may be useful for immune-based or gene therapies.