Plasma Levels of Bacterial DNA Correlate with Immune Activation and the Magnitude of Immune Restoration in Persons with Antiretroviral-Treated HIV Infection
Jiang W, et al. J Infect Dis 2009;199:1177-1185. [PubMed Abstract]

Background:  The CD4 cell decline is central to the immune deficiency associated with HIV infection, but the cause of CD4 depletion is not completely understood.  HIV replicates within these cells and can destroy them, but this does not entirely explain the CD4 depletion.  Further, chronic immune activation does appear to correlate with disease progression and CD4 cell loss (JID 1999;179:859; JAMA 2006;296:1498).  

Purpose:  To investigate the clinical significance of microbial translocation and its association with immune recovery and immune activation in patients with treated and untreated HIV infection. 

Methods:   The study population included 15 persons without HIV infection, 40 patients receiving HAART with high or low HIV viral loads, 19 patients who were treatment-naïve and a cross sectional study of 114 patients.  Studies included assays of microbial translocation by sera measurements of bacterial 16S rDNA and bacterial LPS, and studies of CD8 cell activation with measurements of CD8+CD38+DR+cells.  These were correlated in the various patient populations with viral load and CD4 cell count with and without ARV therapy.

Results:  The following were the observations:

1. Markers of microbial translocation (16S rDNA and LPS) were reduced with ARV treatment vs. untreated patients, but the levels during effective treatment were still higher than in persons without HIV infection.
2. The levels of bacterial DNA correlated with increased levels of immune activation.  
3. Each 100 copies/mL increase in bacterial DNA level was accompanied by a mean reduction of 11 cells/mL recovered.
4. Sequential studies of these parameters at 1, 8, and 48 weeks after HAART showed that markers of microbial translocation, markers of immune activation and HIV viral load decreased with time and CD4 cell counts increased.  However, the markers of microbial translocation were higher at 48 weeks of treatment compared to patients treated over 6 years, suggesting recovery of the gut barrier or better clearance of microbial products with immune recovery.
5. “Modeling of mixed-effects” showed that HAART-associated reduction in HIV viral load and the markers of microbial translocation were negatively associated with the CD4 response, but this correlation was noted at week 48 and not at week 1 or 8 after HAART.  This observation suggests the association between microbial translocation and CD4 cell recovery is correlated with chronic cellular replication and not the first phase of response of CD4 cell counts after beginning HAART.  

Conclusions:  Microbial translocation is correlated with the CD4 cell count dynamics and this is independent of treatment-associated changes in viral load.  Markers of microbial translocation show continued reduction with prolonged HAART, but do not decrease to levels noted in persons without HIV infection even after 6 years of treatment.  Collectively, these observations suggest microbial translocation reflects the loss of the intestinal barrier to microbial products and that this plays an important role in immune deficiency independent of HIV viral load.  

Comment:  The above report tells a potentially important message about the pathophysiology of HIV infection with particular emphasis on the role of the gut barrier as a major factor in  immune activation which appears to contribute to CD4 cell count dynamics independent of HIV viral load.  However, there are some reasons to be skeptical.  Perhaps most disturbing is another report that appeared almost simultaneously, another study from NIAID, (Redd, et al. PNAS 2009;106:6718).  This was a study of the longitudinal relationship of microbial translocation and immune activation done in a cohort of patients in Rakai, Uganda.  In this study, the markers of microbial translocation and immune activation were the same as those used in the study reported above, but they examined the patients before seroconversion and through the course of HIV infection in patients who were classified as non-progressors, standard progressors, or rapid progressors, based on CD4 slope.  In addition, they also measured multiple cytokines.  These longitudinal studies were done in 108 subjects followed for at least 3 years with the conclusion that there was no association between disease progression and cytokine levels or markers of microbial translocation.  One possible conclusion is that HIV infection in Africa is simply different than in the US, but a better explanation is that these divergent observations need further study before any conclusions can be made.  This becomes a central issue to our understanding of the pathophysiology of HIV infection with the recent emphasis on early stage disease characterized by complications that have been attributed to immune activation as noted in the SMART trial.