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D C Montefiori

Publications and source records attributed to D C Montefiori.

At least 91 records · Page 5Linked to original sources
PubMed1996

Human immunodeficiency virus type 1 infection despite prior immunization with a recombinant envelope vaccine regimen.

With efforts underway to develop a preventive human immunodeficiency virus type 1 (HIV-1) vaccine, it remains unclear which immune responses are sufficient to protect against infection and whether prior HIV-1 immunity can alter the subsequent course of HIV-1 infection. We investigated these issues in the context of a volunteer who received six HIV-1LAI envelope immunizations and 10 weeks thereafter acquired HIV-1 infection through a high-risk sexual exposure. In contrast to nonvaccinated acutely infected individuals, anamnestic HIV-1-specific B- and T-cell responses appeared within 3 weeks in this individual, and neutralizing antibody preceded CD8+ cytotoxic responses. Despite an asymptomatic course and an initial low level of detectable infectious virus, a progressive CD4+ cell decline and dysfunction occurred within 2 years. Although vaccination elicited immunity to HIV-1 envelope, which was recalled upon HIV-1 exposure, it was insufficient to prevent infection and subsequent immunodeficiency.

AIDS Vaccines↗
PubMed1996

Neutralizing and infection-enhancing antibody responses to human immunodeficiency virus type 1 in long-term nonprogressors.

Serum antibodies from human immunodeficiency virus type 1 (HIV-1)-infected long-term non-progressors (LTNPs) and non-LTNPs were evaluated for virus neutralization and infection enhancement in vitro. Sera from LTNPs had higher average titers of neutralizing antibodies to HIV-1 strains IIIB and MN and more frequently neutralized primary isolates from progressors (14.9% vs. 1.3%, P = .002). Replication-competent HIV-1 was isolated from peripheral blood mononuclear cells and lymph nodes of 3 LTNPs. All viruses from LTNPs had a non-syncytium-inducing phenotype, were resistant to neutralization by autologous serum obtained at the time of virus isolation, and showed little evidence of a heightened sensitivity to neutralization by heterologous sera. Complement-mediated, antibody-dependent enhancement (C'-ADE) of HIV-1IIIB and primary isolates was equally prevalent for sera from LTNPs and non-LTNPs. Results indicate that LTNPs produce vigorous serum antibody responses and that long-term nonprogression is not associated with homologous neutralization or the absence of C'-ADE.

Adult↗
PubMed1996

An env gene derived from a primary human immunodeficiency virus type 1 isolate confers high in vivo replicative capacity to a chimeric simian/human immunodeficiency virus in rhesus monkeys.

To explore the roles played by specific human immunodeficiency virus type 1 (HIV-1) genes in determining the in vivo replicative capacity of AIDS viruses, we have examined the replication kinetics and virus-specific immune responses in rhesus monkeys following infection with two chimeric simian/human immunodeficiency viruses (SHIVs). These viruses were composed of simian immunodeficiency virus SIVmac239 expressing HIV-1 env and the associated auxiliary HIV-1 genes tat, vpu, and rep. Virus replication was assessed during primary infection of rhesus monkeys by measuring plasma SIVmac p27 levels and by quantifying virus replication in lymph nodes using in situ hybridization. SHIV-HXBc2, which expresses the HIV-1 env of a T-cell-tropic, laboratory-adapted strain of HIV-1 (HXBc2), replicated well in rhesus monkey peripheral blood leukocytes (PBL) in vitro but replicated only to low levels when inoculated in rhesus monkeys. In contrast, SHIV-89.6 was constructed with the HIV-1 env gene of a T-cell- and macrophage-tropic clone of a patient isolate of HIV-1 (89.6). This virus replicated to a lower level in monkey PBL in vitro but replicated to a higher degree in monkeys during primary infection. Moreover, monkeys infected with SHIV-89.6 developed an inversion in the PBL CD4/CD8 ratio coincident with the clearance of primary viremia. The differences in the in vivo consequences of infection by these two SHIVs could not be explained by differences in the immune responses elicited by these viruses, since infected animals had comparable type-specific neutralizing antibody titers, proliferative responses to recombinant HIV-1 gp120, and virus-specific cytolytic effector T-cell responses. With the demonstration that a chimeric SHIV can replicate to high levels during primary infection in rhesus monkeys, this model can now be used to define genetic determinants of HIV-1 pathogenicity.

Animals↗
PubMed1996

Patterns of viral replication correlate with outcome in simian immunodeficiency virus (SIV)-infected macaques: effect of prior immunization with a trivalent SIV vaccine in modified vaccinia virus Ankara.

The dynamics of plasma viremia were explored in a group of 12 simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) that had received prior immunization with either nonrecombinant or trivalent (gag-pol, env) SIV-recombinant vaccinia viruses. Three distinct patterns of viral replication observed during and following primary viremia accounted for significant differences in survival times. High-level primary plasma viremia with subsequently increasing viremia was associated with rapid progression to AIDS (n = 2). A high-level primary plasma virus load with a transient decline and subsequent progressive increase in viremia in the post-acute phase of infection was associated with progression to AIDS within a year (n = 6). Low levels of primary plasma viremia followed by sustained restriction of virus replication were associated with maintenance of normal lymphocyte subsets and intact lymphoid architecture (n = 4), reminiscent of the profile observed in human immunodeficiency virus type 1-infected long-term nonprogressors. Three of four macaques that showed this pattern had been immunized with an SIV recombinant derived from the attenuated vaccinia virus, modified vaccinia virus Ankara. These data link the dynamics and extent of virus replication to disease course and suggest that sustained suppression of virus promotes long-term, asymptomatic survival of SIV-infected macaques. These findings also suggest that vaccine modulation of host immunity may have profound beneficial effects on the subsequent disease course, even if sterilizing immunity is not achieved.

Animals↗
PubMed1996

Simian immunodeficiency virus DNA vaccine trial in macaques.

An experimental vaccine consisting of five DNA plasmids expressing different combinations and forms of simian immunodeficiency virus-macaque (SIVmac) proteins has been evaluated for the ability to protect against a highly pathogenic uncloned SIVmac251 challenge. One vaccine plasmid encoded nonreplicating SIVmac239 virus particles. The other four plasmids encoded secreted forms of the envelope glycoproteins of two T-cell-tropic relatives (SIVmac239 and SIVmac251) and one monocyte/macrophage-tropic relative (SIVmac316) of the uncloned challenge virus. Rhesus macaques were inoculated with DNA at 1 and 3, 11 and 13, and 21 and 23 weeks. Four macaques were inoculated intravenously, intramuscularly, and by gene gun inoculations. Three received only gene gun inoculations. Two control monkeys were inoculated with control plasmids by all three routes of inoculation. Neutralizing antibody titers of 1:216 to 1:768 were present in all of the vaccinated monkeys after the second cluster of inoculations. These titers were transient, were not boosted by the third cluster of inoculations, and had fallen to 1:24 to 1:72 by the time of challenge. Cytotoxic T-cell activity for Env was also raised in all of the vaccinated animals. The temporal appearance of cytotoxic T cells was similar to that of antibody. However, while antibody responses fell with time, cytotoxic T-cell responses persisted. The SIVmac251 challenge was administered intravenously at 2 weeks following the last immunization. The DNA immunizations did not prevent infection or protect against CD4+ cell loss. Long-term chronic levels of infection were similar in the vaccinated and control animals, with 1 in 10,000 to 1 in 100,000 peripheral blood cells carrying infectious virus. However, viral loads were reduced to the chronic level over a shorter period of time in the vaccinated groups (6 weeks) than in the control group (12 weeks). Thus, the DNA vaccine raised both neutralizing antibody and cytotoxic T-lymphocyte responses and provided some attenuation of the acute phase of infection, but it did not prevent the loss of CD4+ cells.

Animals↗
PubMed1995

Studies of complement-activating antibodies in the SIV/macaque model of acute primary infection and vaccine protection.

Questions regarding the potential impact of complement-activating antibodies on lentivirus pathogenesis and vaccine development were addressed in the SIV/macaque model by evaluating sera for activity related to complement-mediated, antibody-dependent enhancement (C'-ADE) of SIV infection in vitro. C'-ADE activity in sera obtained during acute primary infection in macaques inoculated with SIVmac251 appeared before neutralizing antibodies and coincided with the initial peak and decline of plasma antigenemia. The power of C'-ADE activity (i.e., virus production measured by p24 immunoassay) decreased as titers of neutralizing antibodies increased in these animals, suggesting a balance in the net effect between C'-ADE and neutralizing activities in vitro. Antibodies with C'-ADE activity were also induced in macaques immunized with live-attenuated SIVmac239/nef-deletion or primed with recombinant SIVmne gp120 vaccinia virus and boosted with SIVmne rgp160. The titer (i.e., last serum dilution to show enhancement), peak (i.e., serum dilution producing the greatest enhancement as measured by p24 production), and power (i.e., magnitude of p24 production at the peak titer) of C'-ADE activity in sera obtained from vaccinated macaques on the day of challenge were comparable to those of sera from infected macaques and showed no correlation with vaccine outcome, where some protected animals had C'-ADE profiles that resembled those of unprotected animals. The results of these studies suggest that antibodies having C'-ADE activity in vitro could contribute to virus replication or, alternatively, to virus clearance during the acute stage of SIV infection in macaques.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Complement control proteins, CD46, CD55, and CD59, as common surface constituents of human and simian immunodeficiency viruses and possible targets for vaccine protection.

Complement control proteins include a group of membrane-bound surface antigens that protect cells from complement lysis by preventing formation of the membrane attack complex (MAC) of complement. HIV-1 and SIV are known to possess cellular proteins, making it possible that some of them contribute to the ability of these viruses to evade complement lysis. Three complement control proteins, CD46 (membrane cofactor protein), CD55 (decay accelerating protein), and CD59 (HRF20), were found by flow cytometry to be expressed on the surface of CD4+ cell lines commonly used for HIV-1 and SIV synthesis. Monoclonal antibodies to each of these proteins precipitated HIV-1 IIIB and SIV delta/B670 synthesized in CEM x 174 cells and two primary HIV-1 isolates synthesized in peripheral blood mononuclear cells, indicating that CD46, CD55, and CD59 are physically associated with the virus membrane after the virus has been released from the surface of infected cells. Additional experiments showed that the precipitated material contained infectious virus, confirming that whole virus was precipitated. Evidence that CD46 and CD59 are immunogenic in macaques was found when anti-cell antibodies in plasmas from macaques immunized with human cell-grown SIV blocked anti-CD46 and anti-CD59 from binding to the surface of CEM x 174 cells. Anti-cell antibodies rendered HIV-1 susceptible to complement lysis as measured by the release of p24 core protein, and consistently produced a complement-dependent reduction in HIV-1 and SIV infectivity of 1-3 logs. These results demonstrate that CD46, CD55, and CD59 are common surface constituents of HIV-1 and SIV. The results also raise the possibility that the mechanism of SIV vaccine protection attributed to anti-cell antibodies could have involved complement-mediated virolysis.

Antibodies, Viral↗
PubMed1994

Studies of high doses of a human immunodeficiency virus type 1 recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. The AIDS Vaccine Clinical Trials Network.

We examined the safety and immunogenicity of a baculovirus-derived recombinant HIV-1 envelope glycoprotein vaccine candidate, rgp160 (VaxSyn; MicroGeneSys, Meriden, CT), administered at doses of 160 or 640 micrograms to 56 healthy, HIV-1-seronegative adults, in a randomized, double-blind, placebo-controlled study. Immunizations were given intramuscularly at 0, 1, 6, and 12 months. Both doses were generally well tolerated, although self-limited local reactions were frequent. No other clinical or laboratory toxicities were noted, and no effects on CD4 or CD8 lymphocyte counts or percentages were noted. Serum antibody responses to HIV proteins were detected by Western blot (WB) in 19 of 20 and in 19 of 19 recipients of four doses of 160 and 640 micrograms, respectively. Western blot responses developed more rapidly in the 640-micrograms group. High rates of EIA antibody responses to HIV-1 lysate were also present in both groups, and developed more rapidly in the 640-micrograms group. Enzyme immunoassay antibody responses to the immunogen (rgp160) were also frequent, but were infrequent to V3 to gp41 peptides. Neutralizing antibodies against the homologous HIV-1 LAI isolate were seen in 3 of 20 subjects (GMT = 11) who received four doses of 160 micrograms, and in 10 of 19 subjects who received four doses of 640 micrograms (GMT = 32). Fusion inhibiting antibody was not detected. CD4 blocking activity was seen in 3 of 19 subjects who received four doses of 640 micrograms. Complement-mediated antibody-dependent enhancement was found in sera from 11 of 19 volunteers in the 640-micrograms group. Lymphocyte proliferative responses to the immunogen were detected in 4 of 4 subjects tested, but no cytotoxic T cell activity was noted in 11 subjects. Administration of the 640-micrograms dose of this rgp160 vaccine candidate relative to the lower doses was associated with increased immunogenicity, including higher rates of homologous neutralizing antibody responses, although at low titer.

AIDS Vaccines↗
PubMed1994

Binding of human immunodeficiency virus type 1 to the C3b/C4b receptor CR1 (CD35) and red blood cells in the presence of envelope-specific antibodies and complement. National Institutes of Health AIDS Vaccine Clinical Trials Networks.

Immune complexes formed in vitro by incubating cell-free human immunodeficiency virus type 1 (HIV-1) with sera from infected or gp160-vaccinated persons, together with normal human serum as a source of complement, readily bound to K562 cells expressing recombinant human complement receptor type 1 (CR1). However, antibodies from seronegative persons had little or no effect. This effect was absent in the presence of heat-inactivated or C3-depleted normal human sera or when wild type K562 cells were used, confirming a requirement for complement and CR1. In additional experiments, complement alone targeted HIV-1 to CR1 on red blood cells, and envelope-specific antibodies increased this effect. These results demonstrate that envelope-specific antibodies promote HIV-1 immune complex formation with complement and that these complexes readily bind CR1 on cell surfaces.

Antigen-Antibody Complex↗
PubMed1994

Vaccine-induced neutralizing antibodies directed in part to the simian immunodeficiency virus (SIV) V2 domain were unable to protect rhesus monkeys from SIV experimental challenge.

The potential of the simian immunodeficiency virus (SIV) variable 2 (V2) domain as an effective region to boost SIV-neutralizing antibodies and to protect against live SIV challenge was tested in rhesus macaques. In this study, two rhesus macaques were primed with vaccinia virus recombinants expressing the surface glycoprotein gp140 of SIVmac and were given booster injections with the SIVmac V2 domain presented by a highly immunogenic carrier, the hepatitis B surface antigen (HBsAg). The two vaccinated macaques exhibited SIV-neutralizing antibodies after primer injections that were enhanced by the V2/HBsAg injections. Part of these SIV-neutralizing antibodies were directed specifically to the V2 region, as shown by neutralization-blocking experiments. However, despite having consistent SIV-neutralizing antibody titers, animals were not protected against homologous challenge with BK28, the molecular clone of SIVmac251. No SIV envelope-specific cellular cytotoxic response was detected throughout the immunization protocol, suggesting that neutralizing antibodies directed to SIV envelope gp140 and especially to the V2 domain were unable on their own to protect against SIV challenge. Furthermore, the vaccinees seemed to have higher viral loads than control animals after challenge, raising the question of whether neutralizing antibodies induced by vaccination and directed to the SIV envelope selected viral escape mutants, as shown previously in SIV-infected macaques. This mechanism is certainly worthy of intensive investigation and raises some concern for SIV envelope-targeted immunization.

Amino Acid Sequence↗
PubMed1994

Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques.

Infection of the rhesus monkey with simian immunodeficiency virus of macaques (SIVmax) was employed to explore the early immune events associated with the initial containment of an acute AIDS virus infection. In nine rhesus monkeys infected intravenously with uncloned SIVmac strain 251, high-level p27 plasma antigenemia was usually detected transiently from approximately day 7 through day 21 following virus inoculation. SIVmac replication in lymph nodes measured by in situ RNA hybridization closely paralleled the time course and magnitude of viremia. The containment of SIVmac spread by 3 to 4 weeks following infection suggests an efficient, early immune control of this virus infection. Anti-SIVmac antibodies were first detected in the blood at approximately day 14. At the time antigenemia was decreased or cleared, SIVmac neutralizing antibodies were present. A rise in circulating and lymph node CD8+ T cells also occurred coincident with the clearance of antigenemia and persisted thereafter. These CD8+ lymphocytes in lymph nodes had increased expression of both major histocompatibility complex class II and the adhesion molecule LFA-1; they also demonstrated decreased expression of the naive T-cell-associated CD45RA molecule. SIVmac-specific cytotoxic T-lymphocyte precursors were detected in both blood and lymph node by 7 days post-virus inoculation. These studies indicate that both virus-specific humoral and cellular immune mechanisms in blood and lymph node are associated with the clearance of viremia that occurs within the first month of infection of rhesus monkeys with SIVmac.

Animals↗
PubMed1994

Studies of the conformation-dependent neutralizing epitopes of simian immunodeficiency virus envelope protein.

It has been shown previously that the major neutralizing epitopes in simian immunodeficiency virus (SIV) are discontinuous and conformation dependent and that the V3 loop, in contrast to that of human immunodeficiency virus (HIV) type 1, does not by itself elicit neutralizing antibodies (K. Javaherian et al., Proc. Natl. Acad. Sci. USA 89:1418-1422, 1992). We now present data showing that on the basis of fractionation of infected macaque sera, protease digestion of the envelope, and binding properties of two neutralizing monoclonal antibodies to SIV and SIV-HIV chimeric envelope proteins, changes in V3 can disrupt the conformation-dependent neutralization region. The chimeric protein did not produce significant neutralizing antibodies against either SIV or HIV. We also report that neutralizing antibodies elicited by recombinant SIV envelope proteins of mac251 and B670 isolates cross-neutralize. Finally, we show that deglycosylation of the SIV envelope results in a molecule which binds neither soluble CD4 nor the neutralizing monoclonal antibodies being investigated here and does not elicit sera with a significant neutralizing titer.

Acids↗
PubMed1993

Acquired immunodeficiency syndrome-like illness associated with systemic Mycoplasma fermentans infection in a human immunodeficiency virus-negative homosexual man.

A 35-year-old homosexual man developed a composite nodal Kaposi's sarcoma and peripheral T-cell lymphoma that were associated with a peripheral blood CD4-positive lymphocyte count of only 43/mm3. The patient subsequently developed Pneumocystis carinii pneumonitis and eventually died due to disseminated Cryptococcus neoformans. Numerous premortem tests for the presence of human immunodeficiency virus (HIV) types 1 and 2 were negative by the enzyme-linked immunosorbent assay, Western blot, viral isolation, and polymerase chain reaction techniques. Postmortem evaluations for HIV-1, HIV-2, human T-cell lymphotropic virus (HTLV)-I, and HTLV-II also were negative by polymerase chain reaction, immunofluorescence assays, and viral isolation. A systemic infection by Mycoplasma fermentans, however, was documented by immunohistochemistry and polymerase chain reaction in premortem and postmortem tissues. This recently recognized human pathogen has produced systemic infections in patients with the acquired immunodeficiency syndrome (AIDS) and in previously healthy non-AIDS patients who characteristically have a fulminant flu-like illness. Additionally, M fermentans has enhanced the cytopathic effect of HIV in in vitro studies and has produced fatal wasting illnesses with terminal lymphopenia in inoculated adult silvered leaf monkeys. This report is the first description of an association between M fermentans infection and an AIDS-like illness in an HIV-negative individual. The etiology of the severe immunosuppression in this patient and the associated role of M fermentans remain to be determined by further investigations.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Passively transferred antibodies directed against conserved regions of SIV envelope protect macaques from SIV infection.

Inactivated plasma collected from either SIV-infected or peptide-vaccinated macaques was transferred into 17 naive rhesus monkeys. Two additional macaques received normal plasma and served as controls. Following transfer all 19 monkeys were inoculated with SIV. While the controls became infected and were virus-isolation-positive, 3 of 6 recipients of SIV peptide vaccine plasma and 9 of 11 recipients of SIV-infected monkey plasma were protected. None of the 12 protected animals became virus-isolation-positive or seroconverted within 100 days of follow-up. One, however was SIV-PCR-positive. All 12 protected animals were rechallenged 100 days after the initial inoculation; 8 became infected and yielded virus as expected, but 4 remained uninfected. One of the latter was the SIV-PCR-positive monkey mentioned above, suggesting that cryptic SIV infection may be of significance in immunological protection. The results demonstrate that envelope anti-peptide antibodies have similar protective potential in vivo as antibodies directed to the whole virus. In vitro neutralization competition assays performed with sera from vaccinated macaques in the presence of the free peptides suggest that of the four conserved envelope peptides of the vaccine, the two originating from gp41 rather than the two from gp120 are responsible for inducing the neutralizing anti-syncytial activity.

Amino Acid Sequence↗
PubMed1993

Complement-mediated binding of naturally glycosylated and glycosylation-modified human immunodeficiency virus type 1 to human CR2 (CD21).

Particulate glycoproteins lacking sialic acid, such as desialylated enveloped viruses, readily activate complement through the alternative pathway. Human immunodeficiency virus type 1 (HIV-1) contains two heavily glycosylated and partially sialylated envelope glycoproteins: a surface gp120 and a transmembrane gp41. The abilities of naturally glycosylated HIV-1 and glycosylation-modified HIV-1 to interact with the complement system were examined with a biological assay which measured the binding of whole virus particles to cells expressing CR2 (CD21), the complement receptor found naturally in abundance on follicular dendritic cells and immature B cells. HIV-1 IIIB was synthesized in the presence or absence of the mannosidase II inhibitor, swainsonine, to give rise to high-mannose-type, nonsialylated, nonfucosylated carbohydrate moieties. The virus also was treated with neuraminidase or endo-beta-galactosidase to remove terminal sialic acids. An enzyme immunoassay specific for HIV-1 p24 core protein was used to quantitate the amount of virus bound to cell surfaces. Virus particles incubated with 1:3-diluted, fresh HIV-1-negative human serum as a source of complement readily bound to MT-2 (CD4+ CR2+) and Raji-3 (CD4- CR2+) cells but not to CEM (CD4+ CR2-) cells, suggesting that the virus bound to CR2 independently of CD4. Compared with heat-inactivated or C3-deficient sera, fresh complement increased binding by as much as 62 times for naturally glycosylated virus, and 5 times more than this for glycosylation-modified virus. Similar observations were made with freshly isolated, non-mitogen-stimulated peripheral blood mononuclear cells. Additional evidence that HIV-1 bound to CR2 independently of CD4 was provided by the fact that binding was blocked by monoclonal antibody OKB7 (anti-CR2) but not by OKT4a (anti-CD4). Also, the virus bound to transfected K562 cells (CD4-) which expressed recombinant human CR2 but did not bind to untransfected K562 cells. Results obtained with complement component-deficient sera indicated that binding required the alternative complement pathway. Raji-3 and transfected K562 cells could not be infected with HIV-1 in the presence of complement, suggesting that utilization of CR2 as a receptor in the absence of CD4 does not allow virus entry. The demonstration of CR2 as a receptor for HIV-1 in the presence of complement, together with the ability to enhance binding by desialylation, provides new insights into mechanisms of HIV-1-induced immunity and immunopathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1993

V3-specific neutralizing antibodies in sera from HIV-1 gp160-immunized volunteers block virus fusion and act synergistically with human monoclonal antibody to the conformation-dependent CD4 binding site of gp120. NIH-NIAID AIDS Vaccine Clinical Trials Network.

Sera from 11 volunteers immunized with a recombinant HIV-1 gp160-expressing vaccinia virus (HIVAC-1e; Oncogen/Bristol-Myers Squibb, Seattle, WA) and boosted with baculovirus-derived rgp160 (VaxSyn; MicroGeneSys, Inc., Meriden, CT) were evaluated for functional serum antibodies and their epitopes. Sera obtained prior to boosting had undetectable HIV-1-specific IgG and neutralizing activity, and did not block HIV-1 from binding or fusing to CD4+ MT-2 cells. 14 d after boosting, sera from each volunteer contained HIV-1-specific IgG titers of 1:40 to 1:1,280. Five of these sera also contained neutralizing antibodies, where most or all neutralizing activity was blocked by a synthetic peptide corresponding to amino acids 307-330 of the V3 loop of gp120, indicating that neutralizing antibodies were mostly V3 loop-specific. All sera obtained after boosting contained HIV-1 binding/fusion-inhibition antibodies, and a significant portion of their activity was blocked by the V3 loop peptide, a result consistent with the presence of antibodies against the region of the V3 loop that participates in fusion. Three sera with V3 loop-specific neutralizing and fusion-inhibition antibodies were studied further. In competitive antibody binding experiments, antibodies reactive with the conformation-dependent, CD4 binding site of gp120 were undetectable in each serum. When evaluated in combination with a monoclonal antibody to the CD4 binding site of gp120, two sera demonstrated synergism in neutralizing assays, and all three sera demonstrated synergism in binding/fusion-inhibition assays, further indicating that the functional antibodies were primarily V3 loop-specific. The synergism also suggests that a vaccine that elicits strong serum antibody responses to both regions of gp120 may improve the potential for inducing protective immunity.

AIDS Vaccines↗
PubMed1992

Inactivated whole-virus vaccine derived from a proviral DNA clone of simian immunodeficiency virus induces high levels of neutralizing antibodies and confers protection against heterologous challenge.

We tested the ability of macaques vaccinated with inactivated whole simian immunodeficiency virus (SIV) to resist challenge with either homologous or heterologous cell-free uncloned SIV administered by the intravenous route. The vaccine virus was derived from a proviral DNA clone and thus was considered genetically homogeneous. Sixteen macaques received either hepatitis B surface antigen (n = 6) or the inactivated whole-SIV vaccine (n = 10) at weeks 0, 4, and 49 of the study. All SIV vaccine recipients developed high levels of homologous and heterologous neutralizing antibodies in response to vaccination. At the time of challenge (week 53), vaccinees were further stratified to receive either homologous (n = 10) or heterologous (n = 6) uncloned live SIV. The envelope glycoproteins of the homologous and heterologous challenge viruses were 94% and 81% identical to the vaccine virus, respectively. Regardless of challenge inoculum, all vaccinees in the control group (hepatitis B surface antigen) became infected, whereas all SIV vaccinees were protected against detectable infection. These data support the concept that an efficacious vaccine for HIV might be possible, and suggest that genetic variation of HIV might not be an insurmountable obstacle for vaccine development.

Animals↗