T J Matthews

Broadly neutralizing antibodies elicited by the hypervariable neutralizing determinant of HIV-1

The principal neutralizing determinant (PND) of human immunodeficiency virus (HIV)-1 resides within the V3 loop of the envelope protein. Antibodies elicited by peptides of this region were able to neutralize diverse isolates. Serum from one of three animals immunized with the human T cell lymphoma virus (HTLV)-IIIMN PND peptide, RP142, neutralized MN and the sequence-divergent HTLV-IIIB isolate. Serum from one of three animals immunized with a 13-amino acid IIIB PND peptide (RP337) also neutralized both of these isolates. Characterization of these sera revealed that the cross-neutralizing antibodies bound the amino acid sequence GlyProGlyArgAlaPhe (GPGRAF) that is present in both isolates. This sequence is frequently found in the PNDs analyzed in randomly selected HIV-1 isolates. Sera from two rabbits immunized with a peptide containing only the GPGRAF residues neutralized divergent isolates, including IIIB and MN.

EVIDENCE FOR HUMAN INFECTION WITH AN HTLV III/LAV-LIKE VIRUS IN CENTRAL AFRICA, 1959

An individual serum stored since 1959 from Central Africa has been demonstrated reactive against HTLV-III by ELISA Western blotting and by immunoprecipitation against HTLV-III as well as STLV-III. This serum was from a set of 1213 plasmas from various parts of Africa 818 dating from 1959. Because of the known high false positive rates on Abbott EIA in long-term frozen sera those found to be above the cutoff using the formula (mean of 3 negative serum controls plus 10% of the mean of 2 positive serum controls) x 3 were retested by immunofluorescence microscopy and Western blot enzymatic immunoassay. 1 serum taken from Central Africa in 1959 was positive by both tests. This plasma had an OD more than 7 x the cutoff value. It reacted strongly in immunofluorescence with infected H9 cells. Reactivity was detected by Western Blot against all major HTLV-III viral proteins and polypeptide 121. By immunoprecipitation it reacted with all major gag and env encoded proteins of HTLV-III and the gag encoded proteins of STLV-III-AGM. These results suggest that HTLV-III prevalence was low in 1959 but that at least 1 individual was exposed to a similar virus over 25 years ago in Central Africa.

Induction of HIV-1-neutralising and syncytium-inhibiting antibodies in uninfected recipients of HIV-1IIIB rgp120 subunit vaccine.

A recombinant human immunodeficiency virus 1 IIIB (HIV-1IIIB) gp120 subunit vaccine (IIIB-rgp120/HIV-1, Genentech) was tested for safety and immunogenicity in a randomised, double-blind, placebo-controlled phase-I trial. HIV-1-seronegative adult volunteers received three 100 micrograms or 300 micrograms doses of IIIB-rgp120/HIV-1 in alum adjuvant (10 vaccinees in each group), or alum adjuvant alone (8 vaccinees), at 0, 4, and 32 weeks by intramuscular injection. The three injections were well tolerated in both vaccine groups. Antibodies that neutralised homologous HIV-1IIIB were induced in 9 of 10 recipients after three 300 micrograms doses, and 6 of these 9 sera also neutralised heterologous HIV-1SF2. A dose response was evident, since three 100 micrograms injections induced lower titres of HIV-1IIIB neutralising antibodies and in fewer recipients (5 of 9) than the higher dose, with no neutralisation of HIV-1SF2. Similarly, syncytia-inhibiting, CD4-rgp120-blocking, and HIV-1IIIB V3-binding antibodies were induced in a dose dependent manner. Response to the 300 micrograms per dose vaccination occurred in a larger proportion of volunteers and at higher mean titres than seen in previous human trials with other recombinant envelope subunit vaccines or live vaccinia-env priming followed by envelope subunit boosting.

CELLULAR ANTI-GP120 CYTOLYTIC REACTIVITIES IN HIV-1 SEROPOSITIVE INDIVIDUALS

Forty-one patients seropositive for human immunodeficiency virus type 1 (HIV-1) were assessed for cell-mediated cytotoxicity (CMC) against autologous target cells bearing the major envelope glycoprotein of HIV-1, gp120. Effector lymphocytes from over 85% of seropositive patients showed CMC specific for gp120-coated targets, whereas seronegative individuals had no detectable CMC. As a group, symptomless individuals had the highest levels of CMC; patients with AIDS-related complex and AIDS showed progressively diminished reactivity. The gp120-specific CMC was mediated by a population of non-T-cell effectors phenotypically resembling NK/K cells. Cytolysis was not restricted by major histocompatibility complex determinants, as shown by killing of heterologous gp120-adsorbed targets and of HIV-1-infected cell-lines. Gp120-specific CMC was highly augmented in the presence of interleukin 2, so it may be possible to develop therapeutic strategies aimed at destruction of virus-producing cell reservoirs in infected individuals through stimulation of HIV-specific host CMC.

HTLV-III SEROCONVERSION ASSOCIATED WITH HEAT-TREATED FACTOR VIII CONCENTRATE

The prevalence of antibodies to human T-lymphotropic virus type III (HTLV-III) in hemophiliac patients suggests that clotting factor concentrates received by these patients have been contaminated with the virus. The Centers for Disease Control and the National Hemophilia Foundation in the US have recommended the preferential use of heat-treated factor VIII preparations rather than cryoprecipitate plasma or non-heat-treated materials. Preliminary studies have revealed an absence of HTLV-III seroconversion in previously untreated hemophiliacs who received heat-treated products. This letter reports a case of HTLV-III seroconversion in a mild hemophiliac after high doses of heat-treated factor VIII concentrate. The patient a 31-year old man had not received any blood products since 1975. He was admitted to the hospital with a large hematoma in his left leg and an acute compartment syndrome. An emergency 4-compartment fasciotomy was performed after administration of heat-treated factor VIII. Packed red blood cells from HTLV-III-negative female donors were administered. Over the 20-day hospitalization the patient received 99960 units of heat-treated concentrate from 5 different lots obtained from a single manufacturer. 25 days after the operation the patient experienced headache chills malaise photophobia myalgia and fever; cervical lymphadenopathy was noted. 2 weeks later western blot testing indicated HTLV-III seropositivity. It appears that heat treatment failed to inactivate virus and immunity occurred in response to infectious virus. If viral material is present in concontrates heat treatment might inactivate virus but viral antigen might still be present in sufficient amounts to elicit an immune response. Another possibility is passive transfer of HTLV-III antibody. This case illustrates the need for further studies of heat-treated concentrates.

HIV-1 recombinant gp160 vaccine given in accelerated dose schedules

The purpose of this randomized, double‐blind study was to test the safely and immunogenicity of an HIV‐ILAI recombinant gp160 (rgp160) vaccine in healthy, uninfected volunteers using accelerated dosing schedules. Thirty volunteers were randomly assigned lo receive 50μg doses of rgp160 in one of two immunization schedules. Group 1 received rgp160 at times 0, 1, 2 and 5 months: and group 2 received rgp160 at times 0, 1, 2, 3 and 4 months. The vaccine was safe and stimulated high levels of HIV‐1 envelope‐specific binding antibody and T cell memory. There was a trend (P < 0.10) suggesting neutralizing antibodies were better induced by the regimen incorporating a rest period before the final immunization in group 1 volunteers. Both accelerated immunization schedules induced immune responses at levels similar to or better than those achieved by four rgp160 vaccine injections given over 12‐18 months in other studies.

Characterization of Antigens in SSV Nonproducer Cells

An autologous antiserum against simian sarcoma virus (SSV) nonproducer cells (SSV-NP cells) was characterized by radioimmunoprecipitation. It reacts specifically with two different molecules in SSV-NP cells, a SSV transformation-specific glycoprotein (SSV TrS-gp) and p65, which probably represents a modified gag-precursor.