HIV-1 decreases the levels of neurotrophins in human lymphocytes
Avdoshina, Valeriyaa; Garzino-Demo, Alfredob; Bachis, Alessiaa; Monaco, Maria CGc; Maki, Pauline Md; Tractenberg, Rochelle Ee; Liu, Chenglongf; Young, Mary Af; Mocchetti, Italoa
aDepartment of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA
bDepartment of Microbiology and Immunology, Institute of Human Virology, University of Maryland, Baltimore, USA
cLaboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke/National Institute of Health, Bethesda, Maryland, USA
dDepartments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, Illinois, USA
eDepartment of Neurology, USA
fDepartment of Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA.
Received 6 January, 2011
Revised 7 February, 2011
Accepted 4 March, 2011
Correspondence to Italo Mocchetti, PhD, Georgetown University Medical Center, New Research Building WP13, 3970 Reservoir Road NW, Washington, DC 20057, USA. E-mail: firstname.lastname@example.org
Neurotrophins control cell survival. Therefore, we examined whether HIV-1 reduces neurotrophin levels. Serum of HIV-positive individuals exhibited lower concentrations of brain-derived neurotrophic factor (BDNF), but not of other neurotrophins, than HIV-negative individuals. In addition, R5 and X4 strains of HIV-1 decreased BDNF expression in T cells. Our results support the hypothesis that reduced levels of BDNF may be a risk factor for T-cell apoptosis and for neurological complications associated with HIV-1 infection.
Neurotrophins [1,2] are produced by immune organs and immunocompetent cells, including T cells  and macrophages , and are believed to play a role in various functions of the immune system, including lymphocyte proliferation [5,6]. Little is known about the effect of HIV-1 on neurotrophin levels. Loss of neurotrophin expression may impair the immune system and promote AIDS. In this study, we investigated whether HIV-1 reduces serum concentration of the neurotrophins and sought to establish a correlation between HIV infection and neurotrophin expression in T cells.
Serum levels of brain-derived neurotrophic factor (BDNF) were measured by an enzyme-linked immunosorbent assay in human samples collected between 1994 and 2007 at the Washington, District of Columbia site of the Women's Interagency HIV Study [7,8]. Because approximately 50% of these individuals were polydrug abusers, mainly cocaine, methamphetamine and heroin, a two-way analysis of variance (ANOVA) was used to examine a potential interaction between HIV-1 and drug use and to examine each factor independently. HIV-positive individuals exhibited significantly lower levels of BDNF compared with HIV-negative controls (Fig. 1a). Drug use significantly affected BDNF levels such that the amount of BDNF in the serum of HIV-positive drug users were higher than in HIV-positive nondrug users (Fig. 1a), suggesting that polydrug use may affect serum BDNF levels in HIV-1-positive individuals. There was no interaction between drug use and serostatus on BDNF levels (P > 0.33).
Drugs of abuse  or HIV-1 may influence the expression of other neurotrophins. To test this hypothesis, we measured nerve growth factor (NGF) and neurotrophin-3 (NT-3) levels in the same samples. The two-way ANOVAs analyzing associations of HIV status and drug use on NGF (P = 0.516) and NT-3 (P = 0.382) were not statistically significant, and no evidence of interaction between HIV and drug use was observed for either outcome. Although we found a tendency toward lower average NGF levels in the serum of HIV-positive individuals compared with controls, the effect was not significant (P = 0.89) nor did polydrug use affect NGF levels (data not shown). Results for NT-3 levels were similarly not statistically significant (data not shown).
The reduction of BDNF observed in HIV-1-positive individuals could be due to single nucleotide polymorphisms (SNPs) that alter intracellular packaging and secretion of BDNF . rs6265 is a polymorphism in the BDNF gene that produces an amino acid substitution of valine to methionine in codon 66 (Val66Met); rs56164415 is located in the fifth of the seven noncoding exons of the BDNF gene  and appears to be moderately associated with substance abuse . Therefore, these SNPs, either alone or in combination, might lead to a reduction in serum BDNF levels. To test this hypothesis, we examined the frequency of these polymorphisms in the same cohort, using DNA from the same sample of individuals. There was no significant difference in frequency of alleles in HIV individuals as compared with HIV-negative controls (rs6265, P = 0.83; rs56164415, P = 0.72). Therefore, mutation of the BDNF gene does not appear to account for difference in the levels of BDNF in these individuals.
Contributing factors that may account for the decrease in serum BDNF in HIV-positive individuals are not easily defined. BDNF and other neurotrophins are produced by immune organs and immunocompetent cells , as well as platelets . Thus, a decrease in the number of platelets may explain the lower levels of BDNF in HIV-1-positive individuals. To determine whether BDNF from platelets constitutes a significant fraction of serum BDNF, we examined which blood cell type expresses BDNF. We found that platelets and T cells exhibited comparable levels of BDNF expression (Fig. 1b). Thus, platelets account for only for a fraction of serum BDNF. Nevertheless, to more directly examine the effect of HIV-1 on BDNF, we examined the ability of HIV-1 to decrease BDNF expression in T cells. T lymphocytes were prepared from healthy donors and were infected with X4 (IIIB) or R5 (BaL) HIVs. BDNF mRNA levels were then quantified 24 h after the infection. We observed an approximately 50% decrease in BDNF mRNA levels by both HIV-1 strains (Fig. 1c), further suggesting that HIV-1 is capable of reducing the expression of this neurotrophin in T cells.
Our main finding is that the serum of HIV-positive women is characterized by reduced levels of BDNF, but not of NGF or NT-3, irrespective of drug use status, suggesting that HIV-1 influences the expression of selected neurotrophins. This was confirmed by direct evidence that both R5 and X4 HIV-1 strains downregulate BDNF mRNA levels in T cells. These results may contribute new insights into our understanding of the immune dysregulation of AIDS. In fact, given the well known antiapoptotic effect of the neurotrophins for T cells [6,13], we may speculate that a decrease in BDNF could be among the mechanisms employed by HIV-1 to induce apoptosis of T cells. On the contrary, experimental evidence has shown an inverse correlation between levels of BDNF and CXCR4  and CCR5  expression. These coreceptors are crucial for HIV-1 infection . Therefore, reduced levels of BDNF may be a risk factor for increasing HIV infection.
HIV-1 also causes axonal injury, neuronal loss and dementia . BDNF is critical for neuronal survival . Blood neurotrophin levels have been used to investigate the role of the neurotrophins in the pathogenesis of various neurodegenerative diseases. In fact, recent data have shown a relationship between BDNF in blood and Alzheimer's disease  and age-related cognitive impairment . Therefore, serum BDNF could be a predictor of risk for the development of neurological signs in HIV-positive individuals. Our findings of an association between HIV infection and serum BDNF levels, and of lowered BDNF mRNA levels in infected T cells, provide initial evidence in support of this hypothesis and suggest this neurotrophin as a possible biomarker for HIV dementia. Additional studies are needed to validate our results and extend them to both sexes, as we examined a relatively small cohort of women individuals. Also, a link between BDNF and cognitive performance needs to be established.
This study is supported by HHS grants DA026174 (I.M.), NS066842 (A.G.-D.). Women's Interagency HIV Study is funded by UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590, UO1-HD-32632 and UL1 RR024131.
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