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HIV-Induced CD4 Declines Affect Immune Response to HBV in Untreated People
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7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm
Mark Mascolini
Untreated HIV-induced immune suppression slows selection of hepatitis B virus (HBV) reverse transcriptase (RT) and hepatitis B surface antigen (HBsAg) mutations and so may speed HBV disease progression and liver-related mortality in people coinfected with HIV and HBV [1].
That hypothesis emerged from a study of 30 people infected only with HBV and 31 coinfected with HIV-1 and HBV by Valentina Svicher and colleagues in Rome. They undertook this study because genetic evolution of HBV during HIV-driven immune suppression remains largely undefined.
The investigators used Shannon entropy [2] to define HBV RT and HBsAg genetic variability and the nonsynonymous/synonymous substitution (dN/dS) ratio [3] to identify sites under positive selective pressure. They sequenced HBV RT and HBsAg from HBV DNA. No study participants had taken any antivirals for HBV or HIV.
Average age was much higher in the 30 people with HBV infection alone than in the 31 with HBV and HIV (59 versus 40 years). Everyone with HBV alone had HBV genotype D virus, while 5 (13%) of coinfected people had subtype D and 26 (87%) had subtype A. Median HBV viremia stood at 4 log IU/mL (interquartile range [IQR] 2.5 to 5.4) in people infected only with HBV and at 4.5 log IU/mL (IQR 3.7 to 5.9) in coinfected people.
HBV RT and HBsAg genetic variability correlated positively with CD4 count--the higher the CD4 count, the higher the variability (for HBV RT, r = 0.56, P = 0.0001; for HBsAg, r = 0.57, P = 0.0006). In both HBV-monoinfected and HBV/HIV-coinfected people, those with a CD4 count above 600 had the highest genetic variability in both HBV RT (median entropy 0.20, IQR 0.0 to 0.32) and HBsAg (median entropy 0.20, IQR 0.0 to 0.34). As CD4 counts dwindled, HBV RT and HBsAg genetic variability also declined progressively.
Median entropy by CD4 count in RT and HBsAg
• More than 600 CD4s: RT 0.20, HBsAg 0.20
• 300 to 600 CD4s: RT 0.09, HBsAg 0.09
• Fewer than 300 CD4s: RT 0.0, HBsAg 0.0
Multivariate analysis considering patient demographics, CD4 count, HBV genotype, HIV coinfection, and HBeAg status found a significant independent correlation between CD4 count and number of RT mutations (P = 0.002) or HBsAg mutations (P = 0.001). Genotype D versus A did not independently predict HBV variability.
The dN/dS analysis showed that both monoinfected and coinfected people with a CD4 count above 600 had virus that selected unique mutations in the HBsAg a-determinant (crucial for antibody binding) and in the cytotoxic T lymphocyte RT epitopes 107-115, 203-211, and 227-235. In coinfected people, the number of RT sites under positive selective pressure fell progressively as CD4 count fell:
• More than 600 CD4s (6 people): 5 sites under selective pressure
• 300 to 600 CD4s (6 people): 3 sites under selective pressure
• Fewer than 300 CD4s (19 people): 0 sites under selective pressure
Svicher and coworkers concluded that "HIV-related dysfunction downregulates the immune system-driven selection of RT and HBsAg mutations" in untreated people. As the CD4 count falls, immune pressure drops in tandem and immune escape mutations are not selected. This dampened immune response, the investigators proposed, "can accelerate HBV disease progression and thus the risk of liver-related mortality . . . in patients with moderate immune suppression."
References
1. Svicher V, Gori C, Salpini R, et al. HIV-driven immune-suppression modulates HBV evolution in HBV+HIV co-infected patients. 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 37.
2. Shannon CE. A mathematical theory of communication. Bell System Tech J. 1948;27:379-423, 623-656 (http://cm.bell-labs.com/cm/ms/what/shannonday/shannon1948.pdf).
3. Li WH, Wu CI, Luo CC: A new method for estimating synonymous and nonsynonymous rates of nucleotide substitution considering the relative likelihood of nucleotide and codon changes. Mol Biol Evol. 1985;2:150-174.
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