HIV-1 Tat addresses dendritic cells to induce a predominant Th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection.
Tat is an early regulatory protein that plays a major role in human HIV-1 replication and AIDS pathogenesis, and therefore, it represents a key target for the host immune response. In natural infection, however, Abs against Tat are produced only by a small fraction (approximately 20%) of asymptomatic individuals and are rarely seen in progressors, suggesting that Tat may possess properties diverting the adaptive immunity from generating humoral responses. Here we show that a Th1-type T cell response against Tat is predominant over a Th2-type B cell response in natural HIV-1 infection. This is likely due to the capability of Tat to selectively target and very efficiently enter CD1a-expressing monocyte-derived dendritic cells (MDDC), which represent a primary target for the recognition and response to virus Ag. Upon cellular uptake, Tat induces MDDC maturation and Th1-associated cytokines and beta-chemokines production and polarizes the immune response in vitro to the Th1 pattern through the transcriptional activation of TNF-alpha gene expression. This requires the full conservation of Tat transactivation activity since neither MDDC maturation nor TNF-alpha production are found with either an oxidized Tat, which does not enter MDDC, or with a Tat protein mutated in the cysteine-rich region (cys22 Tat), which enters MDDC as the wild-type Tat but is transactivation silent. Consistently with these data, inoculation of monkeys with the native wild-type Tat induced a predominant Th1 response, whereas cys22 Tat generated mostly Th2 responses, therefore providing evidence that Tat induces a predominant Th1 polarized adaptive immune response in the host.
Fanales-Belasio
Emanuele
E
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Moretti
Sonia
S
Fiorelli
Valeria
V
Tripiciano
Antonella
A
Pavone Cossut
Maria R
MR
Scoglio
Arianna
A
Collacchi
Barbara
B
Nappi
Filomena
F
Macchia
Iole
I
Bellino
Stefania
S
Francavilla
Vittorio
V
Caputo
Antonella
A
Barillari
Giovanni
G
Magnani
Mauro
M
Laguardia
Maria Elena
ME
Cafaro
Aurelio
A
Titti
Fausto
F
Monini
Paolo
P
Ensoli
Fabrizio
F
Ensoli
Barbara
B
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005260:Female; D015483:HIV Antibodies / Q000096:biosynthesis; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000276:immunology / Q000502:physiology*
D016915:AIDS Vaccines; D019742:Chemokines, CC; D016207:Cytokines; D015483:HIV Antibodies; D054322:tat Gene Products, Human Immunodeficiency Virus