Boosting of SIV-specific immune responses in rhesus macaques by repeated administration of Ad5hr–SIVenv/rev and Ad5hr–SIVgag recombinants

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

“…Finally, the Tat protein, both intracellular and extracellular, exerts key roles in the pathogenesis of AIDS-associated tumors [100,102] and AIDS-associated neuropathogenesis [103]. The first exon of Tat encodes aminoacids 1-72, which include the N-terminal prolinerich (aa [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], the cysteine-rich (aa 21-37 containing 7 cysteines) and the core (aa 38-48) regions, representing Tat activation domain, and the basic region (aa 49-58) for nuclear localization and binding to the HIV LTR TAR RNAs. The C-terminal region of Tat, comprising the second exon, contains the arginine-glycine-aspartic acid (RGD), which is a motif present in extracellular matrix proteins [104][105][106].…”

“…However, few have provided significant protective immunity in non human primate models [6][7][8][9][10][11][12][13] and, most importantly, results from clinical trials, including the first phase III trial (AIDSVAX carried by VacGen) based on a monomeric gp120 Env protein, have been largely disappointing [14][15][16]. These failures may be ascribed to several reasons, including the fact that i) recombinant monomeric gp120 molecules are insufficient to create the correct antigen conformation for induction of neutralizing antibodies, which indeed recognize mostly conformational epitopes on native trimeric Env proteins, and ii) neutralization sensitive conserved epitopes, mainly located in the V3 region of Env [17], are masked and not accessible to antibodies in native Env proteins because of conformation and heavy glycosylation [18,19].…”

“…In chimpanzee HIV Env-based vaccines and in macaques live attenuated simian immune deficiency virus (SIV) vaccines protected from homologous and heterologous challenge [29][30][31][32][33]. In addition, reduction of viral loads following mucosal challenge with SIV was reported in rhesus macaques primed with recombinant Adenovirures expressing HIV Env and boosted with the recombinant protein [10,13,34]. Passive immunization with anti-Env monoclonal neutralizing antibodies was also shown to be protective against infection, and some monoclonal antibodies, alone or in combinations, were able to neutralize primary HIV-1 strains of different clades in vitro [35][36][37][38][39][40][41][42][43][44][45][46].…”

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

“…Immune escape from vaccineinduced responses had already been shown [85]. Therefore, in order to expand the breadth of immune responses we incorporated an Ad5hr recombinant expressing SIV Gag, optimized as described for HIV-1 gag [86,87] into the immunization regimen [88]. Using both Ad5hr-SIVenv/rev and -SIVgag we showed that priming a second time with identical Ad recombinants did not dampen cellular immune responses -in fact responses to both antigens were boosted as well as anti-SIV Env binding antibodies.…”

“…For example, chimpanzees have been administered 10 7 to 10 8 plaque forming units (pfu) intranasally [77,116,127] while a safe dose in humans is no more than 10 4 [128]. Similarly, using the Ad5hr vector in macaques, doses of 10 9 have been administered intranasally and intratracheally with no clinical consequences [88,93,102]. Duration of shedding of Ad vector in stool samples is also used to estimate Ad replicability in vivo.…”