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Objective: Our objective was to define early virologic and immunologic determinants of human immunodeficiency virus (HIV) type 1 disease progression among 22 case subjects with acute infection from the Trinidad Seroconvertor Cohort., Methods: A linear segmented regression model was fitted to sequential quantitative virus load measurements. Parameters of virus kinetics during different phases of primary infection were correlated with clinical and immunologic end points, by use of Kaplan-Meier estimates and Cox regression., Results: Ten individuals developed acquired immunodeficiency syndrome (AIDS)-defining events. In univariate analysis, progression to AIDS was associated with rate of initial HIV clearance (P=.002), virus load during set point (P=.008), and CD4(+) cell count during steady state (P=.04). In the multivariate analysis, a rapid rate of initial clearance was the sole independent predictor of subsequent progression to AIDS and was associated with a 92% reduction in the risk of AIDS. The rate of initial clearance is inversely correlated with the number of early symptoms (r=-0.66; P=.0008). However, symptoms did not predict subsequent risk of AIDS., Conclusion: Among a subset of patients, rapid clearance of plasma HIV-1 after peak viremia is associated with lower viral set point, prolonged virus suppression before loss of virologic control, and decreased risk of AIDS. These findings are consistent with the hypothesis that effective immune responses during the earliest phase of infection are important determinants of the subsequent natural history.

The extraordinary genetic diversity of human immunodeficiency virus type 1 (HIV-1) is a major problem to overcome in the development of an effective vaccine. In the most reliable animal model of HIV-1 infection, chimpanzees were immunized with various combinations of HIV-1 antigens, which were derived primarily from the surface glycoprotein, gp160, of HIV-1 strains LAI and MN. The immunogens also included a live recombinant canarypox virus expressing a gp160-MN protein. In one experiment, two chimpanzees were immunized multiple times; one animal received antigens derived only from HIV-1LAI, and the second animal received antigens from both HIV-1LAI and HIV-1MN. In another experiment, four chimpanzees were immunized in parallel a total of five times over 18 months; two animals received purified gp160 and V3-MN peptides, whereas the other two animals received the recombinant canarypox virus and gp160. At 3 months after the final booster, all immunized and naive control chimpanzees were challenged by intravenous inoculation of HIV-1SF2; therefore, the study represented an intrasubtype B heterologous virus challenge. Virologic and serologic follow-up showed that the controls and the two chimpanzees immunized with the live recombinant canarypox virus became infected, whereas the other animals that were immunized with gp160 and V3-MN peptides were protected from infection. Evaluation of both cellular and humoral HIV-specific immune responses at the time of infectious HIV-1 challenge identified the following as possible correlates of protection: antibody titers to the V3 loop of MN and neutralizing antibody titers to HIV-1MN or HIV-1LAI, but not to HIV-1SF2. The results of this study indicate that vaccine-mediated protection against intravenous infection with heterologous HIV-1 strains of the same subtype is possible with some immunogens.

A retrospective study of 153 hemophiliacs infected with human immunodeficiency virus-1 (HIV-1) was performed to determine the clinical and immunological consequences of HIV-1 infection and the markers and cofactors associated with these changes. Nearly 80% of HIV-1-infected hemophiliacs have developed a significant reduction in their CD-4+ counts (less than 400 CD-4+ cells/mm3) with 40% having less than 200 CD-4+ cells/mm3 by the end of 1987. The rate of CD-4+ cell count decline was slightly greater in patients who have already developed the acquired immunodeficiency syndrome (AIDS) compared to those who have not (50 vs. 31 cells/mm3/6 months). Thrombocytopenia and older age were associated with a more rapid CD-4+ count deterioration, but the quantity of clotting factor utilized did not affect immunologic progression. In patients with less than 200 CD-4+ cells/mm3, the incidence of AIDS was significantly higher in adults (greater than 21 years old) compared to children/adolescents. Cytomegalovirus (CMV) seroprevalence increased with age but did not correlate with the amount of concentrated clotting factor used. Although there was no relationship between CMV status and progression to AIDS, CMV-seropositive patients were older and had a lower CD-4+ count. Thus the majority of HIV-1-infected hemophiliacs are developing progressive immune dysfunction measured by CD-4+ count decline. This drop in CD-4+ count significantly correlates with a risk for the development of AIDS in adults but not in children (less than 21 years old).

In a 6-week clinical trial 4 dose regimens of 3'-azido-3'-deoxythymidine (AZT), a thymidine analogue with potent anti-viral activity against HTLV-III in vitro, were examined in 19 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). AZT was given intravenously for 2 weeks, then orally for 4 weeks at twice the intravenous dose. AZT was well absorbed from the gut and crossed the blood-brain barrier. Therapeutic levels were maintained with 5 mg given intravenously or 10 mg given orally every 4 h. Treatment was not limited by side-effects, the commonest of which were headaches and depression of white-cell counts. 15 of the 19 patients had increases in their numbers of circulating helper-inducer T lymphocytes (p less than 0.001) during therapy, 6 who were anergic at entry showed positive delayed type hypersensitivity skin test reactions during treatment, 2 had clearance of chronic fungal nailbed infections without specific anti-fungal therapy, 6 had other evidence of clinical improvement, and the group as a whole had a weight gain of 2.2 kg. Also, with the highest dose regimen cultures of peripheral blood mononuclear cells for HTLV III became negative.

Cytophilic antibodies which mediate antibody dependent cellular cytotoxicity (ADCC) against envelope antigens of human immunodeficiency virus (HIV) can be found in seropositive individuals. In these experiments, sera from a wide spectrum of HIV infected patients ranging from asymptomatic to overt acquired immunodeficiency syndrome (AIDS) were shown to contain high titers of antibodies that mediate ADCC. Not only did patient antibodies bind to surface expressed viral antigens and mediate ADCC against cells chronically infected with human T-lymphotropic virus type IIIB (HTLV-IIIB), but also against cells infected with the divergent HTLV-IIIRF2 and HTLV-IIIMN viral isolates. Similar results were obtained with target cells bearing purified GP 120 from HTLV-IIIB and HTLV-IIIRF2, indicating that a major portion of the activity was mediated by anti-GP 120 antibodies. Consistent with this was the ability to absorb most of the group-specific ADCC activity from the serum of an HIV infected individual using affinity columns bearing purified HTLV-IIIB GP 120. The finding that human antibodies reactive against the HIV envelope glycoprotein mediate ADCC against cells chronically infected with divergent strains of HIV will have important implications in designing rational approaches to passive and active immunotherapy.

The lymphocyte differentiation antigen CD4 serves as a receptor for human retroviruses associated with acquired immunodeficiency syndrome (AIDS) through its interaction with the major envelope virion glycoprotein, gp120, which is also expressed on the surface of infected cells. In these experiments, purified gp120 was shown to bind to normal human T-lymphocyte populations. The gp120-CD4 complex served as a target antigen for antibody-dependent complement-mediated cytolysis by a goat serum raised against native gp120. However, patient sera that bound to gp120-adsorbed cells failed to direct their destruction in the presence of complement. In contrast, these sera were potent mediators of antibody-dependent cellular cytotoxicity. These studies demonstrate that gp120 situated on the cell surface can serve as an effective target for immune destruction by patient antibodies and effector lymphocytes. The possible contribution of this type of immunity to control of disease progression, on the one hand, and to lymphocyte destruction and immunopathology observed in AIDS, on the other, is discussed.

In efforts to identify B cell and T cell epitopes of HIV-1 structural components, serum as well as lymphocytes from HIV-1-seropositive individuals were reacted with several recombinant and native peptides representing defined viral gag and env determinants. Several areas of discordance between humoral and cellular reactivity were identified. Specifically, the principal neutralizing site within HIV-1, the major envelope glycoprotein gp120, failed to elicit detectable cellular reactivities. The carboxyl portion of gp120 and the transmembrane gp41 region were uniformly recognized by patient antibodies but did not produce significant lymphocyte blastogenesis. However, the amino half of gp120 elicited cellular responses in a majority of the immunocompetent individuals tested, despite its extremely low reactivity with patient sera. Last, the major HIV-1 structure component p24 was found to be the most consistent T cell activation antigen among the panel tested.

To examine the variables associated with heterosexual transmission of human immunodeficiency virus (HIV), we studied 32 couples in our hemophilia center who had steady sexual relationships for periods more than 1 year. Of the 32 sexual partners of the hemophiliacs, five (15.6%) were HIV seropositive. All five hemophiliacs with HIV transmission to their sexual partners had measurable immunologic deficiencies, as shown by their lower median T-helper (CD-4+) lymphocyte count of 172 cells/mm3. The hemophiliacs without transmission had a slightly higher median CD-4+ count of 297 cells/mm3 (P = .26). To determine if factors other than the degree of immunologic deficiency in the hemophiliac might contribute to HIV transmission, 18 of the 32 couples were studied more intensively by confidential, coded questionnaires. Regular condom use was reported by nine couples (50%). Two of nine women (22%) without condom usage acquired HIV. One of nine women (11%) using condoms was seropositive; she also reported eight needlestick injuries while assisting her spouse with clotting factor treatments. Intravenous drug abuse was reported in two of the five couples with HIV transmission. Thus, hemophiliacs are at risk for transmitting HIV parenterally as well as venereally. Despite various risk behaviours associated with HIV transmission, the prevalence of infection in our cohort of hemophiliacs' sexual partners is low and within the range (6.8-22%) reported by others. This study underscores the need for comprehensive education and counseling in what previously appeared to be a homogeneous clinic population at risk for transmitting HIV to others.

A 17-month-old boy in whom immune-mediated thrombocytopenia (ITP) was the presenting manifestation of infection with human immunodeficiency virus (HIV) is being successfully managed with intermittent high-dose intravenous gamma globulin (IVIG) allowing maintenance of hemostatic platelet counts while avoiding the immunosuppression associated with other therapeutic modalities used to treat ITP. He continues to demonstrate marked responsiveness to IVIG, and has been maintained on weekly or bimonthly infusions for 12 months. The serendipitous documentation of HIV infection prior to IVIG therapy for immune-mediated thrombocytopenia in this child documents the importance of HIV testing prior to IVIG therapy to prevent erroneous assignment of IVIG as the vehicle responsible for transmission of HIV infection. This case history also documents the importance of HIV testing in the diagnostic evaluation of immune-mediated thrombocytopenias.

The magnitude of immunologic defects observed in HIV-1-infected individuals before the development of overt AIDS is disproportionately high in comparison to the levels of infectious virus in these patients--suggesting that factors other than direct virus-induced cytopathology may be involved. With this in mind, we investigated the immunologic consequences of the interaction between purified HIV-1 gp120 and the CD4 molecules expressed by uncommitted as well as Ag-specific lymphocytes. HIV-1 gp120 exhibited a dose-dependent immunosuppressive effect on: 1) Ag-driven proliferation of cloned CD4+ lymphocytes, 2) OKT3-driven proliferation of cloned CD4+ lymphocytes, and 3) cytolytic activity of CD4+, EBV-specific CTL. Thus, HIV-1 gp120 can, in a manner similar to OKT4A antibodies, suppress T cell activation and the expression of cytolytic activities through its interaction with CD4. Additionally, activated CD4+ lymphoblasts can be rendered susceptible to immune cytolysis by virtue of their binding of purified gp120. This "targeting" of activated lymphoblasts can occur with levels of gp120 far below that which is needed to saturate all OKT4A-defined CD4 epitopes. Adsorbed gp120 could be demonstrated on the surface of these cells for up to 12 h, a sufficient time for interaction with host cytolytic elements. The data from these in vitro modeling experiments highlight one of many potential mechanisms of HIV-1 induced immunosuppression and lymphocyte destruction that can occur in the absence of infectious virus and that is based on the unique interaction between HIV-1 gp120 and its cellular receptor, CD4.