HIV cannot be eradicated and keep latent in anatomical and cellular reservoirs. In fact, patients undergoing antiretroviral treatment (ART) interruption rapidly experience plasma viral load rebound. The current alternative therapeutic strategies to antiretroviral treatment have the aim to achieve the eradication or permanent remission of plasma viral load, also known as functional cure, in the absence of ART, as occurs in persistent HIV controllers. In this scenario, new drugs associated to ART that allow the achievement of permanent plasma viral remission after ART withdrawn are studied.
The main targets of HIV infection are the memory CD4+ T-cells. This cell subset is mainly located in gut associated lymphoid tissue (GALT). These lymphocytes are recruited to the gut thanks to the expression of the integrin α4β7. The Env protein gp120 binds to α4β7 and enable the dissemination of HIV in the gut. At the same time the envelope of HIV is enriched in α4β7 coming from the plasma membrane of the host cells favoring its pathogenicity. The administration of a monoclonal antibody against α4β7 was shown to achieve significant protection for HIV transmission before and after low dose intravaginal inoculation of SIV in Rhesus Macaques (Byrareddy et al., Nat Med 2014). Surprisingly, anti-HIV bNAbs and anti- α4β7 mAb combined treatments delayed rebound viremia in SHIV-infected macaques suggesting beneficial immune modulatory activity during the infection that complements the effect of anti-HIV bNAbs (Frank et al., Sci. Transl. Med 2021). These findings make the antibody against α4β7 a good candidate as ART adjuvant with the aim to reach a functional cure and/or persistent virological remission in humans. There is a monoclonal antibody against α4β7 with known safety and security profiles in humans; this antibody is commercially available under the name of Vedolizumab. The first clinical trial administering Vedolizumab therapy combined with cART in early stages of infection in naïve HIV-infected subjects for ART was developed in our hospital, Virgen del Rocio Hospital (Sevilla, Spain). The aim was to evaluate the safety and efficacy of Vedolizumab combined with ART to achieve permanent virological remission in naïve HIV-infected individuals after ART interruption. Ten patients were enrolled during acute infection. The subjects started cART together with Vedolizumab infusion (300mg), at week 24 both treatment were interrupted. Vedolizumab was well tolerated and no adverse events occurred. Despite no dramatic virological remission after ART interruption was found in naïve subjects this clinical trial provide valuable information about de reservoir establishment in peripheral blood and GALT. α4β7-expression was associated with higher reservoir levels. In addition, correlations between some immune check point molecules and α4β7-expression in CD4 T cells were observed in peripheral blood and tissue. These results provide a rationale for future studies involving Vedolizumab as a potential adjuvant in therapeutic regimens to achieve HIV-1 functional cure (Jimenez-Leon et al., CROI 2022; Abstract 359).
Mª Reyes Jimenez-León and Ezequiel Ruiz-Mateos
Instituto de Biomedicina de Sevilla (IBiS)
Hospitales Universitarios Virgen del Rocio