Susan Zolla-Pazner

Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial

BACKGROUND In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case-control analysis to identify antibody and cellular immune correlates of infection risk. METHODS In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up. RESULTS Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P=0.02; q=0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P=0.03; q=0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies. CONCLUSIONS This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.

Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 monoclonal antibodies.

ABSTRACT Broadly neutralizing monoclonal antibodies (MAbs) are potentially important tools in human immunodeficiency virus type 1 (HIV-1) vaccine design. A few rare MAbs have been intensively studied, but we still have a limited appreciation of their neutralization breadth. Using a pseudovirus assay, we evaluated MAbs from clade B-infected donors and a clade B HIV+ plasma against 93 viruses from diverse backgrounds. Anti-gp120 MAbs exhibited greater activity against clade B than non-B viruses, whereas anti-gp41 MAbs exhibited broad interclade activity. Unexpectedly, MAb 4E10 (directed against the C terminus of the gp41 ectodomain) neutralized all 90 viruses with moderate potency. MAb 2F5 (directed against an epitope adjacent to that of 4E10) neutralized 67% of isolates, but none from clade C. Anti-gp120 MAb b12 (directed against an epitope overlapping the CD4 binding site) neutralized 50% of viruses, including some from almost every clade. 2G12 (directed against a high-mannose epitope on gp120) neutralized 41% of the viruses, but none from clades C or E. MAbs to the gp120 V3 loop, including 447-52D, neutralized a subset of clade B viruses (up to 45%) but infrequently neutralized other clades (≤7%). MAbs b6 (directed against the CD4 binding site) and X5 (directed against a CD4-induced epitope of gp120) neutralized only sensitive primary clade B viruses. The HIV+ plasma neutralized 70% of the viruses, including some from all major clades. Further analysis revealed five neutralizing immunotypes that were somewhat associated with clades. As well as the significance for vaccine design, our data have implications for passive-immunization studies in countries where clade C viruses are common, given that only MAbs b12 and 4E10 were effective against viruses from this clade.

Disseminated Kaposi's Sarcoma in Homosexual Men

Nineteen cases from an epidemic of disseminated Kaposis sarcoma in homosexual men were studied by clinical, virologic, immunologic, and genetic methods. The patients were all male homosexuals ranging in age from 29 to 52 years, with histories of multiple sexually transmitted diseases and exposure to both prescription and recreational drugs. Sites of disease included skin (16 of 19 patients), lymph nodes (13 patients), gastrointestinal tract (12 patients), spleen (three patients), and lung (one patient). Most patients had elevated levels of serum immunoglobins, positive antibody titers to hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus, and impairment of cell-mediated immunologic reactions. The frequency of HLA-DR5 in these patients was significantly elevated. Two of the 19 patients died. Although the precise cause of this epidemic is unknown, it is likely that a genetic predisposition, an acquired immunoregulatory defect, and one or more infectious agents and drugs may be involved.

Identifying epitopes of HIV-1 that induce protective antibodies

During the past 20 years, the pendulum of opinion in the HIV-1 vaccine field has swung between two extremes, initially favouring the induction of antibodies only, and subsequently favouring the induction of cell-mediated immune responses only. At present, the consensus seems to be that induction of both humoral and cellular immunity by an HIV-1 vaccine will be required to achieve maximum protection. One obstacle to the development of an effective HIV-1 vaccine has been the difficulty in inducing broadly reactive, potent antibodies with protective functions. Defining epitopes and designing immunogens that will induce these antibodies is one of the main challenges that now confronts the HIV-1 vaccine field.

Mycobacterium avium-intracellulare: A Cause of Disseminated Life-Threatening Infection in Homosexuals and Drug Abusers

Five men developed disseminated infection with Mycobacterium avium-intracellulare. These patients all lived in the New York City area and presented with their illnesses between January 1981 and September 1981; four were homosexual and one was an intravenous drug abuser. Four patients died. All five patients had defects in the cell-mediated immune response. The infections were characterized histopathologically by poor or absent granulomatous tissue reaction. Clinical isolates of M. avium-intracellulare from all five patients agglutinated commonly used antimycobacterial drugs. The spectrum of opportunistic infections among populations of homosexuals and drug abusers should be expanded to include disseminated disease due to M. avium-intracellulare.

A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.

BACKGROUND Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.

Immunologic abnormalities in homosexual men: Relationship to Kaposi's sarcoma☆

Studies were performed to define the immunologic status of various groups of homosexual men including homosexual men with Kaposis sarcoma, healthy homosexual men who were of similar ages to the homosexual patients with Kaposis sarcoma and homosexual men with hyperplastic lymphadenopathy. Heterosexual men with Kaposis sarcoma were also studied. Immunologic parameters which were examined included serum immunoglobulin levels, enumeration of B cells, T cells, and T-cell subsets, and quantitation of lymphocyte responsive to phytohemagglutinin (PHA) and pokeweed mitogen (PWM). Significant immunologic abnormalities were observed in all three groups of homosexuals studied. These were most severe in the homosexuals with Kaposis sarcoma, somewhat less severe in homosexual men with lymphadenopathy, and least marked but still significant in healthy homosexual men. Heterosexual men with Kaposis sarcoma displayed essentially normal immunologic profiles. The possible etiologic factors underlying the immunologic abnormalities in the male homosexual population studied and the role of an altered immune system in the development of and the fulminant course of Kaposis sarcoma in these patients are discussed.

Vaccine-Induced Env V1–V2 IgG3 Correlates with Lower HIV-1 Infection Risk and Declines Soon After Vaccination

A V1-V2 IgG3 response to HIV correlates with a decreased risk of HIV-1 infection and is one vaccine-induced humoral response that is higher in a clinical trial showing HIV-1 vaccine efficacy compared to a trial showing nonefficacy. Env IgG3 Takes Center Stage Only one HIV-1 vaccine trial (RV144), to date, has demonstrated some level of vaccine efficacy. IgG antibodies to the V1-V2 region of the HIV-1 envelope correlated with decreased HIV-1 risk. However, a previous vaccine trial (VAX003) also induced these types of antibodies but failed to demonstrate efficacy, thus raising the question about whether the quality of the V1-V2 IgG response and the context of other immune responses were important. Yates et al. report that these two trials did induce a qualitatively distinct antibody subclass response, with more V1V2 IgG3 responses and correlations with antiviral function induced by the partially efficacious RV144 vaccine regimen compared to the VAX003 vaccine regimen that lacks efficacy. The authors then demonstrated that these specific IgG3 antibodies correlated with a decreased risk of infection in a placebo-controlled, blinded study of RV144 vaccinees with and without subsequent HIV-1 infection. Vaccine-induced HIV-1 antibody subclass profiles, specifically Env IgG3, should be evaluated in future HIV-1 vaccine efficacy trials to further refine immune correlates of protection. HIV-1–specific immunoglobulin G (IgG) subclass antibodies bind to distinct cellular Fc receptors. Antibodies of the same epitope specificity but of a different subclass therefore can have different antibody effector functions. The study of IgG subclass profiles between different vaccine regimens used in clinical trials with divergent efficacy outcomes can provide information on the quality of the vaccine-induced B cell response. We show that HIV-1–specific IgG3 distinguished two HIV-1 vaccine efficacy studies (RV144 and VAX003 clinical trials) and correlated with decreased risk of HIV-1 infection in a blinded follow-up case-control study with the RV144 vaccine. HIV-1–specific IgG3 responses were not long-lived, which was consistent with the waning efficacy of the RV144 vaccine. These data suggest that specific vaccine-induced HIV-1 IgG3 should be tested in future studies of immune correlates in HIV-1 vaccine efficacy trials.

The V1/V2 Domain of gp120 Is a Global Regulator of the Sensitivity of Primary Human Immunodeficiency Virus Type 1 Isolates to Neutralization by Antibodies Commonly Induced upon Infection

ABSTRACT A major problem hampering the development of an effective vaccine against human immunodeficiency virus type 1 (HIV-1) is the resistance of many primary viral isolates to antibody-mediated neutralization. To identify factors responsible for this resistance, determinants of the large differences in neutralization sensitivities of HIV-1 pseudotyped with Env proteins derived from two prototypic clade B primary isolates were mapped. SF162 Env pseudotypes were neutralized very potently by a panel of sera from HIV-infected individuals, while JR-FL Env pseudotypes were neutralized by only a small fraction of these sera. This differential sensitivity to neutralization was also observed for a number of monoclonal antibodies (MAbs) directed against sites in the V2, V3, and CD4 binding domains, despite often similar binding affinities of these MAbs towards the two soluble rgp120s. The neutralization phenotypes were switched for chimeric Envs in which the V1/V2 domains of these two sequences were exchanged, indicating that the V1/V2 region regulated the overall neutralization sensitivity of these Envs. These results suggested that the inherent neutralization resistance of JR-FL, and presumably of related primary isolates, is to a great extent mediated by gp120 V1/V2 domain structure rather than by sequence variations at the target sites. Three MAbs (immunoglobulin G-b12, 2G12, and 2F5) previously reported to possess broad neutralizing activity for primary HIV-1 isolates neutralized JR-FL virus at least as well as SF162 virus and were not significantly affected by the V1/V2 domain exchanges. The rare antibodies capable of neutralizing a broad range of primary isolates thus appeared to be targeted to exceptional epitopes that are not sensitive to V1/V2 domain regulation of neutralization sensitivity.

Association of human immunodeficiency virus infection and autoimmune phenomena

Patients infected with human immunodeficiency virus have a variety of presentations including fevers, lymphadenopathy, rash, renal dysfunction, and neurologic and hematologic disorders. Many of these features are also seen in patients with systemic lupus erythematosus (SLE). Herein are described five patients ultimately diagnosed as having acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) in whom the differential diagnosis included SLE because of multi-system disease and autoimmune phenomena, especially positive antinuclear antibodies. Serum samples from 151 consecutive patients with AIDS or ARC were examined and 19 with low titer-positive antinuclear antibodies were found (17 at 1:20 and two at 1:160). These observations suggest that SLE and human immunodeficiency virus infection may share clinical and serologic features.