AIDS Reviews 2007;9 140 Molecular and Cellular Interactions of HIV-1/HTLV Coinfection and Impact on AIDS Progression Claudio Casoli 1 , Elisabetta Pilotti 1 and Umberto Bertazzoni 2 1 Department of Clinical Medicine, Nephrology , and Health Sciences, University of Parma, Italy; 2 Department of Mother and Child, Biology and Genetics, University of Verona, Italy Abstract In the last 10 years HIV-1/human T-cell leukemia virus (HIV-1/HTLV) coinfection has emerged as a worldwide health problem. The numbers of HIV-1/HTLV-1 coinfections in South America and Africa are increasing, as well as HIV-1/HTLV-2 coinfections in the USA and Europe. Coinfections by either HTLV-1 or HTLV-2 and HIV-1 frequently occur in persons with a history of injection drug use. Since HTLV-1 preferentially infects CD4+ T-cells and HTLV-2 has a tropism for CD8+ T-cells, the influence of coinfection on HIV-1 disease progression may be different. The effect of HIV-1/HTLV-1 coinfection on HIV-1 pathogenesis is controversial as soluble factors pro- duced by HTLV-1 infected cells can either enhance or suppress HIV-1 infection. In HTLV-1/HIV-1 coin- fected patients, upregulation of HIV-1 expression was attributed to strong activation of cytokines that promoted HIV infection. The introduction of HAART has dramatically reduced HIV-1 morbidity and mortality, but has given rise to an increased number of inflammatory syndromes. While HAART is suc- cessful for controlling HIV disease, it has little impact on HTLV-1/2 genome expression. The conse- quence of coinfection, even with HAART, may well be the reported increase in neurologic disease. Several epidemiologic and in vitro studies of the influence of HTLV infection on HIV-1 related AIDS progression suggest that HTLV-1 infection can promote HIV-1 replication and accelerate the clinical progression to AIDS. However, other studies have not confirmed these observations. The differences in study outcomes could be related to the occurrence of different HIV-1 phenotypes in clinical disease. In contrast, evidence points to a confirmed protective role of HTLV-2 that is manifested as improved survival and delayed progression to AIDS. The protective effect may be the result of maintaining nor- mal-range levels of CD4 and CD8 counts, lowering HIV replication, and immune activation. As a corol- lary, the number of long-term nonprogressors for AIDS in the HIV-1/HTLV-2 coinfected group was found to be significantly higher than in HIV-1 monoinfected cases. Investigations of the natural factors induced by HTLV-2 that influence HIV-1 replication show that CCL3L1 (an isoform of CCL3) is preferentially in- duced in HTLV-2 exposed seronegative HIV individuals and in long-term nonprogressor HTLV-2/HIV-1 coinfected persons. The CCL3L1 inhibits HIV replication and thus acts as a potent effector against both HIV infection and disease progression. As a complement to upregulation of CCL3L1, other chemokines and cytokines induced by HTLV-2 may contribute to induction of the Th1 response against invading pathogens, in contrast to the dominant Th2 response that appears to favor HIV infection. The number of individuals with either single HIV-1 or HTLV-2 infection, in a cohort of Italian intrave- nous drug users monitored for 20 years, decreased significantly over time. However, the magnitude of HTLV-2 decrease was significantly less than that of HIV-1, pointing to the need for increased at- tention to, and control of, HTLV infection. AIDS Rev. 2007;9:140-9 Correspondence to: Umberto Bertazzoni University of Verona Section of Biology and Genetics Strada Le Grazie, 8 27100 Verona, Italy E-mail: umberto.bertazzoni@univr.it No part of this publication may be reproduced or photocopying without the prior written permission of the publisher © Permanyer Publications 2010