The HIV pandemic has claimed more than 25 million lives since the discovery of the virus in 1983. To date, two genetically related but distinct human lentiviruses, HIV-1 and HIV-2, have been described [1,2]. Although both viruses share similar transmission routes, cellular targets and AIDS causatives, HIV-2 infection is generally characterized by a much longer asymptomatic stage, lower plasma viral load, slower decline in CD4+ T-cell counts, and lower risk of mortality [3–6].
In West Africa, where HIV-2 is epidemic, dual infection with HIV-1 and HIV-2 has been reported with a prevalence of 0–3.2% [7,8]. In 1995, Travers et al.  reported on a possible protective effect of HIV-2 against subsequent HIV-1 infection in commercial sex workers in Senegal. Subsequent studies from other cohorts in West Africa could not verify this finding [10–14]. Studies of the natural disease progression among HIV-1 and HIV-2 dual-infected individuals have in most cases not been able to demonstrate any difference in disease progression rate between HIV-1 single and HIV-1 and HIV-2 dual-infected individuals. However, these studies have been limited by low numbers of study participants, short follow-up times or long intervals between visits, or lack of information of estimated infection date (reviewed in ). In addition, most of the studies followed hospitalized patients with advanced disease at enrolment. In contrast, we recently showed that HIV-1 and HIV-2 dual-infected individuals had a 50–90% longer progression time to AIDS as compared to the general HIV-1-infected case by studying an occupational cohort of police officers from Guinea-Bissau followed annually for more than 20 years and with estimated dates of HIV-1 infection . Interestingly, the inhibition was strongest, and only statistically significant, among patients with an HIV-2 infection preceding the HIV-1 infection, suggesting a potential priming effect of HIV-2 in preparing the immune system for a future and more aggressive HIV-1 infection. Moreover, the results showed that CD4+ T-cell counts decreased and HIV-1 diversity increased at a similar rate in both groups, but at different levels, indicating that determinants of differences in disease outcome may be related to events in early HIV-1 infection.
To examine whether mortality rates also differed between HIV-1 single and HIV-1 and HIV-2 dual-infected individuals, Prince et al.  recently performed a meta-analysis of available data from different West African cohorts. No significant difference in mortality rates was found in that study. In the current study, we aimed to compare survival times of HIV-1 single and HIV-1 and HIV-2 dual-infected individuals in a cohort with long and frequent follow-up and with estimated dates of HIV-1 infection.
A prospective open cohort of police officers in Guinea-Bissau was followed from February 1990 to February 2011 [8,16]. It has continuously included new participants except for temporary closure from June 1998 until the end of 2002 as a result of the civil war in 1998–1999. However, annual controls of previously included individuals were resumed already in July 2000. All persons with regular employment in the Guinea-Bissau police force were eligible for the study, which has been voluntary with more than 98% participation frequency (the number of police officers who accepted to be included in the study). Blood samples for serology and CD4+ T-cell counts were collected at inclusion and at follow-up visits scheduled at intervals of 12–18 months. The number of individuals lost to follow-up during the study period was defined as the number of individuals censored at a time equal to or more than 3 years before the study end (Table 1). Antiretroviral therapy (ART) was introduced in Guinea-Bissau in 2005 through a national treatment program, and the few study participants receiving ART had data censored from the time-point of ART initiation (Table 1). Date of seroconversion of HIV-1 was estimated as the mid time-point between the last HIV-1-seronegative sample and the first HIV-1-seropositive sample.
Diagnostic laboratory methods
Serological HIV testing was performed at the National Public Health Laboratory (LNSP), Bissau, as described in detail in Supplemental Digital Content and http://links.lww.com/QAD/A471 in [8,16,19]. Evaluations of the HIV antibody testing strategy have shown a high concordance between the results obtained by serology and by PCR, and a high degree of distinction between HIV-1 and HIV-2 [19,20]. In addition, serology of sequential samples of the same infected individuals was without discrepancies, which further strengthens the results of this strategy. The screening assays have been evaluated in parallel to ensure reproducibility between assays .
Survival analysis was performed for mortality. Cases that did not reach event during follow-up were right-censored at their last examination date or when ART was initiated. Kaplan–Meier curves were generated for graphical presentation. A Cox proportional-hazards model was applied, adjusting for sex and age at seroconversion. To control that the proportional-hazards assumption was satisfied, we analysed log-minus-log plots to rule out any crossing of the curves.
Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, New York, USA).
The study was approved by Ethics Committees of Guinea-Bissau Government, Guinea-Bissau; University of Lund, Lund, Sweden; and the Karolinska Institute, Stockholm, Sweden. Study participants were counselled and provided informed verbal consent.
A total of 259 HIV-1-seroincident individuals were analysed in this study. Among those, 223 were infected by HIV-1 only (185 men, 37 women and one with missing sex status; referred to as single-infected individuals), and 36 with both HIV-1 and HIV-2 (29 men and seven women; dual-infected individuals) (Table 1). The median age at HIV-1 seroconversion was 36 years [interquartile range (IQR) 30–45] for single and 41 years (IQR 34–46) for dual-infected individuals. The median estimated date of HIV-1 infection was 17 October 2001 (IQR 14 May 1998–29 November 2005) for single and 7 December 1997 (IQR 24 July 1994–10 May 2000) for dual-infected individuals (P < 0.001, Mann–Whitney U-test). During the study period, 47 single (21%) and six dual-infected individuals (17%) (P = 0.66, two-tailed Fisher's exact test) were considered to be lost to follow-up (Table 1, for detailed analysis about loss to follow-up see Supplemental Digital Content, http://links.lww.com/QAD/A471). Among the dual-infected individuals, 13 had a simultaneous recorded dual seroreactivity (HIV-D0→D) and 23 had an HIV-2 seroreactivity preceding the dual seroreactivity (HIV-D2→D). The HIV-D0→D-group could represent a heterogeneous group with three potential infection scenarios: HIV-1 preceding the dual infection, HIV-2 preceding the dual infection, or simultaneous HIV-1 and HIV-2 infection. In the cohort, three individuals had HIV-1 seroreactivity recorded before HIV-1 and HIV-2 dual seroreactivity. These individuals were excluded from this study due to the limited number of individuals.
Kaplan–Meier survival analysis for all-cause mortality showed a median survival time of 11.3 years [95% confidence interval (CI) 9.9–12.7 years] for dual-infected individuals compared with 8.2 years (95% CI 7.5–8.8) for single-infected individuals (P = 0.072, log-rank test). A Cox proportional-hazards regression model controlling for age and sex at HIV-1 seroconversion showed significant adjusted mortality hazard ratios for both infection group and age at seroconversion. However, reanalysis of the data including interaction terms showed a significant interaction between these covariates (P = 0.023) (Table 2). This implied that the effect of dual infection vs. HIV-1 single infection on mortality differed between age groups, making the hazard ratios of the individual covariates difficult to interpret in the analysis of the full dataset. Inspection of data showed that a large proportion (25%) of the single-infected individuals were under 30 years of age at HIV-1 seroconversion, whereas only a small proportion of the dual-infected (3 individuals) were under 30. The median age was also higher in the dual group (41 vs. 36 years at HIV-1 seroconversion). To adjust for this skewness of age between the groups, we reanalysed the data including only individuals above 30 years at HIV-1 seroconversion. This dataset included 167 single-infected individuals (145 men and 22 women), median age 40 years (IQR 35–48); and 33 dual-infected individuals (26 men and seven women), median age 41 years (IQR 35–47). The median survival time was 8.0 years (95% CI 7.3–8.7) for the single and 11.3 years (95% CI 9.5–13.0) for the dual-infected individuals (P = 0.012, log-rank test, Kaplan–Meier analysis). The adjusted hazard ratio comparing single vs. dual-infected individuals was 2.56 (95% CI 1.34–4.90, P = 0.005) controlling for age and sex at HIV-1 seroconversion (Table 2). In this analysis, age did not appear as a significant variable (P = 0.20) and there was no significant interaction between age and infection group (P = 0.17) (Table 2). In addition to the infection group, sex also had a significant effect on survival (men vs. women) in the analysis of individuals above 30 years at HIV-1 seroconversion (hazard ratio 2.55, 95% CI 1.04–6.28, P = 0.041) (Table 2). However, a nonsignificant interaction between infection group and sex (P = 0.15) suggested that mortality was lower both in dual-infected individuals and women, independent of each other (Table 2).
To evaluate the effect of infection order among individuals over 30 years of age at HIV-1 seroconversion, we stratified the dual group into those with HIV-2 seroreactivity preceding the dual seroreactivity (HIV-D2→D, n = 22) and those with a simultaneous recorded dual seroreactivity (HIV-D0→D, n = 11). Kaplan–Meier analysis showed that HIV-D2→D-infected individuals had a longer survival time [median estimate 11.3 years (95% CI 10.0–12.5)] than the single-infected group [8.0 years (95% CI 7.3–8.7), P = 0.034, log-rank test] (Fig. 1a). The survival time for the HIV-D0→D-infected individuals [12.0 years (95% CI 5.0–18.9)] did not differ significantly from either the HIV-D2→D group (P = 0.90, log-rank test) or the single group (P = 0.097, log-rank test). The adjusted hazard ratio (controlling for age and sex) in single vs. HIV-D2→D-infected individuals was 2.40 (95% CI 1.17–4.89, P = 0.016, Wald test) and in single vs. HIV-D0→D-infected individuals 3.12 (95% CI 0.95–10.28, P = 0.062, Wald test) (Table 2). The hazard ratio of HIV-D0→D vs. HIV-D2→D-infected individuals was 0.77 (95% CI 0.21–2.79, P = 0.69, Wald test). No significant interaction terms were found (Table 2).
To further investigate the effect of sex and age on our initial analysis of the entire dataset, we compared survival times between single and dual-infected men (the largest sex group in our dataset) among individuals over 30 years at HIV-1 seroconversion. This dataset included 145 single [median age 40 years (IQR 35–48)] and 26 dual-infected individuals [median age 43 years (IQR 36–48)]. The median survival time was 8.0 years (95% CI 7.3–8.7) for the single and 11.7 years (95% CI 10.2–13.2) for the dual-infected individuals (P = 0.001, log-rank test, Kaplan–Meier analysis). The adjusted hazard ratio comparing single vs. dual-infected individuals was 3.76 (95% CI 1.71–8.27, P < 0.001) controlling for age at HIV-1 seroconversion (Table 2). No significant interaction term was found (Table 2). The stratified analyses showed that both the HIV-D2→D (n = 17) and the HIV-D0→D-infected individuals (n = 9) had a longer survival time [median estimates 10.6 years (95% CI 8.8–12.4) and 12.0 years (95% CI 5.0–18.9)] compared to the single group [8.0 years (95% CI 7.3–8.7), P = 0.006 and P = 0.025, respectively, log-rank test] (Fig. 1b). The survival time for the HIV-D0→D and the HIV-D2→D group did not differ significantly (P = 0.93, log-rank test). The adjusted hazard ratio (controlling for age) in single vs. HIV-D2→D-infected individuals was 3.82 (95% CI 1.56–9.36, P = 0.003, Wald test) and in single vs. HIV-D0→D-infected individuals 3.63 (95% CI 1.07–12.36, P = 0.039, Wald test) (Table 2). The hazard ratio of HIV-D0→D vs. HIV-D2→D-infected individuals was 1.05 (95% CI 0.27–4.13, P = 0.94, Wald test). No significant interaction term was found (Table 2).
In this cohort of police officers, mortality data on HIV-related death was also collected. Discrepancies between the all-cause mortality data and the HIV-related mortality data were few (four percent of the single and three percent of the dual-infected individuals died of non-HIV-related causes and were therefore right-censored at their last follow-up date in the analysis of HIV-related mortality). Analysis of the data according to HIV-related mortality gave similar results as the analysis of the all-cause mortality data (for details, see Supplemental Digital Content, http://links.lww.com/QAD/A471).
Our observations that the survival time is longer and the risk of progression to death is lower among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals indicate that HIV-2 has a natural inhibitory effect on HIV-1 disease progression rate in vivo. These results, based on unique HIV-1 incident data combined with high follow-up rates and long follow-up times (more than 20 years of cohort study period), are in line with a previous study in which we showed that dual-infected individuals with a preceding HIV-2 infection had a longer progression time to AIDS than HIV-1 single-infected individuals . In the current study, we show that this inhibitory effect was significant also for dual-infected individuals with a simultaneously recorded HIV-1 and HIV-2 infection.
The hypothesis of a cross-reactive and protective effect against HIV-1 by the less pathogenic, but closely related HIV-2 has been debated [8–14,21]. In strong support of our population-based results, experimental studies using the macaque model have shown inhibition against both immunosuppression and simian immunodeficiency virus-induced disease due to contemporaneous HIV-2 infection [22,23]. There could be several explanations for this inhibition. In our previous study, we showed that the CD4+ T-cell counts decreased and HIV-1 diversity increased at similar rates in single and dual-infected individuals, but that the levels of CD4+ T-cell counts was higher and the diversity lower at a given time-point after HIV-1 infection in the dual-infected individuals. Even though a possible continuous effect could not be excluded, these results indicated that determinants for the difference in disease outcome between single and dual-infected individuals likely were related to events during the primary HIV-1 infection .
Several in-vitro studies have investigated possible cross-reactive mechanisms between HIV-1 and HIV-2: HIV-2 infection generates high levels of β-chemokines in peripheral blood mononuclear cells, which has been shown to inhibit HIV-1 infection and replication [24–27]; T-cell samples from single HIV-1 and HIV-2-infected individuals have shown high frequencies of heterologous cross-reactivity ; both HIV-1 single and HIV-1 and HIV-2 dual-infected individuals with the ability to respond to the HIV-2 Gag protein have been shown to have lower HIV-1 plasma viral loads compared to those without this cross-reactivity [28,29]; and HIV-2-elicited antibodies have shown the ability to cross-neutralize HIV-1 .
Most (23 out of 36) of the HIV-1 and HIV-2 dual-infected individuals in our study had an HIV-2 single infection preceding the HIV-1 infection, and the majority of these were HIV-2-seroprevalent at study entry. There could have been a selection against HIV-2-infected individuals with a fast disease progression due to the development of AIDS or death at an early stage after infection (i.e. this group never became dual-infected since they did not ‘have enough time’ to encounter HIV-1). Both the likelihood of contracting an HIV-1 infection and the likelihood of inclusion in our cohort increase the longer an HIV-2-infected individual remains disease-free. Assuming that the underlying mechanism(s) that conveys the inhibitory effect against disease progression in HIV-2 infection conveys a similar inhibitory effect against disease progression in HIV-1 infection, the dual-infected group could, at least in part, potentially represent a selected group of HIV-1 long-term disease controllers. It is well known that HIV-2 single-infected individuals in general progress much slower (if at all) to AIDS and it has been suggested that only about 20–30% of HIV-2 single-infected individuals do progress to AIDS . The described selection process could therefore act to exclude, at a maximum, the 20–30% of individuals with fastest progression time to AIDS from the dual-infected group. In order to control for this potential bias in our cohort, we recently performed a simulation analysis . The analysis clearly showed that selection for long-term disease controllers in the dual group could not explain the difference in disease progression rate between the HIV-1 single and HIV-1 and HIV-2 dual-infected individuals. In addition, it is important to emphasize that 13 of the 36 (36%) dual-infected individuals were recorded to be HIV-1 and HIV-2-positive at the same health examination control. Consequently, this group could not have been selected for any long-term disease control. Finally, some of the dual-infected individuals with a previous HIV-2 single infection preceding the HIV-1 infection already displayed partial immunodeficiency at the time of HIV-1 infection. These patients would act conservative in the Kaplan–Meier comparison between single and dual-infected individuals. On the basis of these analyses, we find it unlikely that any potential selection of disease controllers could explain the difference in survival between the HIV-1 single and HIV-1 and HIV-2 dual-infected individuals.
In a recently published meta-analysis, Prince et al.  compared mortality rates between HIV-1 single and HIV-1 and HIV-2 dual-infected individuals based on data from six previous studies. The authors did not find any significant difference between the groups and concluded that there is no evidence in dual-infected individuals that HIV-2 infection impedes the progression of HIV-1 infection. However, the majority of the data used by Prince et al. was extracted from studies not designed for comparing survival between single and dual-infected individuals . The major limitations were lack of information on estimated infection date, short periods of follow-up or observation time of individuals (0.5–3 years), and lack of information on infection order among dual-infected individuals. One of the studies did have a longer observation time (maximum 20 years), but was instead limited by few follow-up visits with long intervals (7–10 years) . Another crucial limitation was that most of the data were collected from hospitalized participants with advanced HIV disease already at enrolment. In addition, in many of the studies, the dual-infected individuals were older than the HIV-1 single-infected individuals at enrolment (up to 16 years difference in median estimates) .
Since the 1990s, the prevalence of HIV-2 in West Africa has decreased, whereas that of HIV-1 has increased [10,34–36]. As a consequence, dual-infected individuals are likely to have been infected with HIV-1 earlier in time than the average HIV-1 single-infected individual. This was also confirmed in our cohort, where dual-infected individuals were infected by HIV-1 on average 3.9 years earlier than the single-infected individuals. It is reasonable to believe that a similar difference in infection dates also exists in other West African cohorts, although this cannot be confirmed without known infection dates. This would imply that dual-infected individuals are likely to have carried their HIV-1 infection longer, on average, than HIV-1 single-infected individuals at enrolment in seroprevalent cohorts (without knowledge on HIV infection date), causing a systematic bias towards a faster disease progression among dual-infected individuals.
As described above, we previously showed that the rate in CD4+ T-cell decline was similar between single and dual-infected participants, but that the levels at intercept (estimated infection date) were significantly different, explaining the longer progression time to AIDS among dual-infected individuals . This clearly illustrates the importance of information on infection date, frequent sampling, and long follow-up when comparing HIV-1 single and HIV-1 and HIV-2 dual-infected individuals. Similar baseline characteristics in terms of CD4+ T-cell levels and disease progression would likely obscure any potential difference between the groups irrespective of whether the end-point is time to AIDS or mortality. Therefore, it is not surprising that Prince et al.  did not find any difference in mortality rates between the groups. Their results do not contradict our current or previous results . Instead, the similar mortality rates in HIV-1 single and HIV-1 and HIV-2 dual-infected individuals when measured from similar baseline characteristics indirectly confirm our result of a similar disease progression rate (as measured by CD4+ T-cell decline) in the two groups . One limitation of the generalization of our results is that the majority of the study participants were men (83%). Unfortunately, we did not reach enough statistical power to perform a reliable evaluation on the effect of HIV-2 inhibition on HIV-1 disease progression stratified by sex.
To summarize, our results clearly show that HIV-1 and HIV-2 dual-infected individuals have a longer survival time and are at a lower risk of progression to death compared to HIV-1 single-infected individuals. These conclusions are built on the largest cohort of single and dual-infected individuals followed from estimated date of infection to death that has been presented. Further investigations of the interplay between HIV-1 and HIV-2 or of any systemic immunologic effects of a contemporaneous HIV-2 infection on HIV-1 pathogenesis could reveal new and critical mechanisms important for the development of future vaccines or therapeutics.
We thank Babetida N’Buna, Aquilina Sambu, Eusebio Ieme, Isabel da Costa, Jacqueline Pereira Barreto, Ana Monteiro Watche, Cidia Camara, Braima Dabo (deceased), Carla Pereira, Julieta Pinto Delgado, Leonvengilda Fernandes Mendes, Ana Monteiro, Ansu Biai, Fransisco Dias, Anders Nauclér, Gunnel Biberfeld, Sören Andersson, Helen Linder for their contributions to this work.
Author contributions: J.E. analysed the data and wrote the manuscript. J.E., F.M., H.N. and P.M. interpreted the data and were responsible for the overall study design and over sight of the project. F.M. and H.N. clinically evaluated the patient data. J.E. performed the survival analyses. J.E., A.K. and P.E.I. contributed in statistical analyses. F.M., H.N. and A.J.B. were medically and organizationally responsible for the clinical sites with biological samples of the study participants in the cohort. Z.J.d.S. was responsible for analyses of HIV serology at the laboratory in Guinea-Bissau. M.J. and E.M.F. participated in interpretation of the results. J.E., A.K. and P.M. finalized the manuscript. All authors read and approved the manuscript.
Funding: Swedish Research Council, the Swedish International Development Cooperation Agency/Department for Research Cooperation (SIDA/SAREC), the Crafoord Foundation, Lund, Sweden, the Royal Physiographic Society, Lund, Sweden, The Lars Hierta Memorial Foundation, Stockholm, Sweden, and Konsul Thure Carlsson Fund for Medical Research, Lund, Sweden and the Tegger Foundation for Research at Widespread Diseases.
Conflicts of interest
The authors declare that they have no conflict of interest.
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