HIV and HTLV-1 have emerged as common co-pathogens especially in areas or groups where both viruses are circulating [5
]. Nevertheless, the impact of HTLV-1 on HIV disease progression is still a matter of debate with controversial results [10
]. Here, for the first time we conducted a case control study in an African setting, aiming to determine the impact of HTLV-1 infection on HIV disease. In fact, to our knowledge, the present study is pioneer in the region, since it was conducted in HAART naïve patients, on a well controlled cross-sectional basis.
Previous studies were conducted mainly in South and North Americas where the epidemiology of HIV infection and other diseases is quite different from that seen in sub-Saharan African countries [29
We found no evidence of HTLV-2 in our study population. This is in keeping with two recent studies conducted among blood donors in Maputo city[34
] and suggest that only HTLV-1 (but not HTLV-2) circulates in Mozambique.
As expected, co-infected individuals presented a stable CD4+
T lymphocytosis irrespective of their progression to AIDS, contrasting with the depletion of CD4+
T cells counts observed among HIV patients over time. To date, it is well established that cell immortalization and transformation induced by Tax and Rex proteins encoded by HTLV-1 genes constitute major events related to uncontrolled CD4+
T cell growth and proliferation [41
The intriguing progression to AIDS in the presence of normal or high levels of CD4+T cells counts suggest these to be functionally altered. Consensus exists that both HIV [43
] and HTLV [24
] separately induce functional modifications on T cells populations, characterized among others by a decrease of naïve populations and higher levels of cell activation when compared with uninfected individuals.
Here we found that co-infected individuals presented markedly lower expression of CD45RA+
(a phenotypic marker of naïve T lymphocytes) on CD4+
T cells. Naïve cells are considered the first cells to be depleted in the presence of immune activation [46
] and represent one of the hallmarks of HIV infection [48
]. The magnitude and impact exerted by naïve T cells erosion on HIV disease progression remain to be defined. Although not fully understood, there is a consensus that for both HIV and HTLV-1, the loss of naïve cells has been linked, among others, to, (i) a homeostatic mechanism to replenish the cells being killed (ii) a massive recruitment of naïve cells, partially imposed by the mechanisms driving the activation and (iii) the impairment of T cell production [19
In our study, the erosion of the naïve compartment was further confirmed by evaluating the expression of CD62L, another marker for naïve T lymphocytes, usually lost upon activation. As expected, there was a dramatic loss of CD4+CD62L+ lymphocytes in the co-infected group, when compared to HIV mono-infected and HC groups. Importantly, these differences were further confirmed when we compared the groups in terms of naive cell absolute counts (data not shown) arguing against an indirect effect of higher percent counts of memory cells. Whether there is an impairment of T cell production, if they are dying faster or if more cells being recruited from the naïve T cell pool into activated/memory cell compartment remain to be determined.
Not surprisingly, this loss of naïve cells in co-infected individuals was accompanied by higher frequencies of memory and activated cells as measured by CD45RO+
(activated) cell markers. In fact, co-infected individuals presented with higher proportions of CD45RO+
T cells when compared to the HIV and HC groups. These findings are in agreement with previously data [45
], Similarly, the relative number of CD4+
cells seen in co-infected patients was higher than what was found in HIV and HC individuals. It is conceivable that the increase of CD4+
cells is a consequence of the virus-driven induction of IL-2/IL-2 receptor expression by tax, as previously reported [12
]. Interestingly, the frequency of CD38+
cells within the CD8+
T cell compartment but not in CD4+
T cells was increased in co-infected and HIV when compared to HC. This is in keeping with the results showed in a case-control study conducted among HAM/TSP patients [24
]. Although we did not find differences in the frequency of CD38+
cells, either in CD8+
T cells, we found that co-infected patients presented higher expression of CD38 in CD8+
T cells (as ascertained by Median Fluorescence Intensity measurements) when compared to HIV patients. Nevertheless differences were not statically significant.
Noteworthy, increased expression of CD38 on the surface of CD8+
T cells have long been considered an even better prognostic predictor of progression to AIDS and response to HAART than HIV viral load itself [53
]. This is relevant due to the fact that such parameter is being proposed to be included in clinical settings to monitor HIV disease progression [55
It is now widely accepted that the presence of chronic activation is a major factor influencing the pathogenesis of HIV in Africa [56
]. HTLV-1 is a strong activator of immune system. Immune activation and exaggerated immune response has been demonstrated to be the main pathogenetic mechanism involved in the HTLV-1 associated inflammatory syndromes[24
]. The immunodominant Tax protein encoded by HTLV transactivates and modulates a large number of genes playing a key role in triggering several pathways leading to cell activation[60
]. Available data demonstrate that a large proportion of asymptomatic carries progress with high levels of immune activation[63
On the basis of the patients' age and their HAART naïve status, we believe that HTLV-1 infection preceded HIV infection. Considering that individuals chronically infected by HTLV progress with immune activation, it is conceivable that these patients acquire HIV infection in a pre-activated immune milieu, and the presence of immune hyper activation not only turns them more susceptible to acquire HIV, but also to progress faster to a poor prognosis.
Cases and controls were matched by age and clinical stage (WHO) so that to be comparable in terms of clinical presentation (see table ), Clinical staging system is performed on the basis of patient's clinical presentation. This information is important when interpreting the differences in the activation markers between these groups. Another aspect deserving discussion is the helminthic infection as a factor involved in immune activation, particularly in Southern Africa [3
]. Accordingly, a differential presence of parasitic infection in our patients could bias our results. However, this does not seem to be the case since in all groups evaluated, the degree of protozoan and helminthic infections were similar. Of note, all samples sequenced in both groups were founded to be HIV subtype C, ruling out any linkage between HIV subtype in mono and co-infected groups, and immunological/clinical behavior.