Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Abstract

HIV-1-specific monoclonal antibodies (mAbs) with extraordinary potency and breadth have recently been described. In humanized mice, combinations of mAbs have been shown to suppress viremia, but the therapeutic potential of these mAbs has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific mAbs, as well as the single glycan-dependent mAb PGT121, resulted in a rapid and precipitous decline of plasma viremia to undetectable levels in rhesus monkeys chronically infected with the pathogenic virus SHIV-SF162P3. A single mAb infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa, and lymph nodes without the development of viral resistance. Moreover, following mAb administration, host Gag-specific T lymphocyte responses exhibited improved functionality. Virus rebounded in the majority of animals after a median of 56 days when serum mAb titers had declined to undetectable levels, although a subset of animals maintained long-term virologic control in the absence of further mAb infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific mAbs in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of mAb therapy for HIV-1 in humans.

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

“…36 Similarly, passive infusions of one or more bNAbs resulted in complete virological suppression in simian/human immunodeficiency virus (SHIV)-infected macaques, with no evidence of viral escape. 37,38 Viral rebound in both the humanized mice and macaques occurred only after decline in serum bNAb levels. [36][37][38] Compared with the delivery of recombinant bNAbs, vectored bNAbs may circumvent the need for frequent reinjections by enabling sustained, high levels of transgene expression.…”

“…37,38 Viral rebound in both the humanized mice and macaques occurred only after decline in serum bNAb levels. [36][37][38] Compared with the delivery of recombinant bNAbs, vectored bNAbs may circumvent the need for frequent reinjections by enabling sustained, high levels of transgene expression. Although bNAbs can be vectored in AAV, 9,10 AAV has a limited carrying capacity 12 that would necessitate multiple vectors and injections if combinations of bNAbs were to be administered.…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…Some individuals, elite neutralizers, can elicit broadly neutralizing antibodies that recognize conserved regions of the virus envelope protein [168]. The presence of these broadly neutralizing antibodies is not associated with a dramatic control of viraemia in vivo, but has been shown to strongly decrease viraemia when administered to SHIVinfected macaques [169]. Neutralizing IgAs have been found in the genital tract of different cohorts of highly exposed but seronegative females [170,171], suggesting that these antibodies contribute to protection from AIDS acquisition in these subjects.…”

Les anticorps anti-VIH-1 et la transmission virale de cellule à cellule

“…Des résultats spectaculaires ont aussi été récemment obtenus chez l'animal (chez le singe ou chez la souris humanisée) [8][9][10]. L'administration passive de bNAb de nouvelle génération, ou leur sécrétion dans la circulation sanguine par des vecteurs de type adeno-associated virus (AAV), induit un effet antiviral thérapeutique ou prophylactique.…”