Limited data exist regarding the viral dynamics of HIV-1 and HTLV-1/2 viral co-infection in vitro [Lin et al., 1995
; Cheng et al., 1998
; Moriuchi et al., 1998
; Nekhai et al., 2007
]. One study suggested that a factor or factors secreted by HTLV-1 could enhance replication of HIV-1 in vitro [Moriuchi et al., 1998
]. Sun et al. 
demonstrated that HIV-1-mediated syncytium formation promoted cell-to-cell transfer of HTLV-1 Tax protein with subsequent activation of the HTLV-1 transcription. De Rossi et al. 
conducted experiments suggesting that superinfection of HTLV-1 infected cells with live HIV-1 activated HTLV-1 viral expression but not the tat protein, whereas the current study has suggested that tat protein and PMA has a combined effect on HTLV p19 expression.
In this study, exposure to either HIV-1 or the HIV-1 Tat protein increased the number of both HTLV-1 and HTLV-2 infected cells () which is a result of both increased infectivity and increased productivity, as evident from the number of positive cells () and the total level of p19 expression (). There was a significant increase in HTLV-1 positive cells at 24 hr post-infection and the amount of both IFA positivity () and subjective staining intensity were shown to peak at 120 hr (5 days) post-infection.
The IFA experiments demonstrated a preferential replication of HIV-1 within HTLV-1/-2 infected cells. This suggests the possibility that HIV-1 and HTLV-1/-2 interact dynamically within the same cells in vivo. Co-localization of HIV-1 and HTLV-1 or -2 within the same cells would support the contention that HIV-1 itself and/or associated HIV-1 gene products are responsible for the observed increase in HTLV-1/-2 expression. Interestingly, the cells that were determined to be HIV-1 positive were nearly always HTLV-1 positive as well, and only in rare cases were HIV mono-infected cells observed.
In clinical samples, previous experiments documented higher levels of HTLV-1/-2 tax/rex
mRNA in PBMC samples from HTLV-1/-2 and in subjects dually infected with HIV [Beilke et al., 1997
]. The current experiments corroborate this finding, and suggest the possibility that HIV-1 Tat protein, released by the infected cells, may play a dominant role in increasing HTLV-1 infectivity and p19 expression. A number of previous studies have documented the possible role of other transcription factors and second messenger signaling pathways activated in different cell types following exposure to HIV-1 Tat protein [Bohan et al., 1992
; Zauli et al., 1992
; Hui et al., 2006
]. Exogenously added Tat protein can have similar inductive effect as compared to the infectious HIV-1, suggest that Tat may activate HTLV-1 proviral activation. This is clearly indicative of the time dependent increase in HTLV-1 p19 expression by both HIV-1 virions and recombinant Tat protein. Since activation of HIV-1 and HTLV-1/2 provirus is under the control of both viral regulatory genes as well as cellular transcription factors [Ensoli et al., 1993
; Lin et al., 1995
; Hui et al., 2006
], the possibility exists that HIV-1 Tat can activate the HTLV-1 long terminal repeat (LTR), either directly or via cooperation with cellular co-factors [Nakhai et al., 2007]. The rapid increase in p19 expression, which occurred within 24 hr following exogenous addition of Tat protein, in contrast to the peak observed at 3–5 days with HIV virions, also indicates that the delayed effect may be due to the time required to establish HIV infection and Tat protein expression. The presence of HIV virions only in productively HTLV-1/2 infected cells suggests that such an augmented effect may occur predominantly in co-infected cells. Nonetheless, the current experiments cannot exclude the possibility that HIV-1 induction of HTLV-1 expression is due to a paracrine effect of HIV-1 (or HIV-Tat) on neighboring cells.
The observation that PMA-stimulation of cultures enabled a significant increase in Tat mediated increase in p19 expression also suggests that activated cellular factors may be necessary for optimal initiation and propagation of the co-infection cycle. The PKC pathway is potently stimulated by PMA, and specific PKC isozymes are activated during a number of inflammatory stimuli [Aksoy et al., 2004
; Hayashi et al., 2007
] occurring in co-infected reservoirs, due to immune activation and cytokine expression. HIV-1 co-infection may further cause activation of inflammatory signaling via PKC, so it is possible that in addition to Tat, PKC-inducible cellular factors could mediate activation of HTLV-1/2 infectivity.
While the current investigations provide evidence that HIV-1 and Tat protein may upregulate HTLV-1/2 expression, the study does not fully address the prior observation that HIV disease progression is delayed in patients with HIV/HTLV co-infections [Beilke et al., 1994
]. The proliferative effects of HTLV-1/2 infection may prevent the lytic HIV cycle from depleting the host lymphocytes. As seen with severe HTLV-1 disease presented as adult T cell leukemia/lymphoma or HTLV-2 disease presented as TSP/HAM, promotion of cell division is a prominent feature of HTLV-1/2 pathogenesis [Blattner, 1994
; Gallo, 2002
]. Established HTLV-1/2 models account for this proliferative effect in the pathogenesis of HTLV-1/2 [Cheng et al., 1998
; Gallo, 2002
]. In addition to proliferation, another potential mechanism focuses on similar gene homology of HTLV-1/2 Tax and HIV Tat proteins [Hui et al., 2006
]. These gene products may interact at similar molecular pathways and sequester specific transcription factors, thus enabling a competition between both viruses. A productive infection by one virus may also alter disease progression and potentially enable HTLV-1/2 or HIV to replicate at altered rates. However, further work on viral dynamics, both in vivo and in vitro will be needed to test these hypotheses. The findings from these viral dynamics studies may have probable significance in generating alternative strategies to suppress productive co-infection and regulate disease progression by either viruses.