HIV Enters and Injures Brain Early

	SUMMARY: Structure and function changes in the brain are evident early in the course of HIV infection and are linked to inflammation, researchers reported at CROI 2011.

By Paul Dalton

Both clinical and laboratory research have shown that HIV injures the brain. As the focus of much research shifts to the long-term consequences of HIV infection, interest in the brain has grown. Several presentations at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) dealt with the effects of HIV on both brain structure and function.

Early Infection

In a talk titled "HIV Brain Viral and Inflammatory Signatures During Acute HIV infection," Victor Valcour of the University of California San Francisco (abstract 54) presented results from a study looking at measures of HIV and inflammation in the brains of people infected with HIV for less than 6 months. These individuals were compared to a matched group of chronically HIV infected people as well as a group of uninfected controls.

Results

	HIV was found in the brain of all participants.
	50% of participants reported headaches during HIV seroconversion, although there was no correlation with levels of HIV in the brain.
	HIV levels were around 2.5 logs lower in cerebral spinal fluid (CSF) than in plasma.
	Several but not all makers of inflammation were higher in acutely infected people.
	This inflammatory pattern peaked during the second and third of four stages prior to seroconversion (called Freiberg stages).

This study shows that HIV is present at the earliest stages of HIV infection and leads to early inflammation in the brain. A better understanding of when and how HIV enters the brain should help both researchers and clinicians better deal with the effects of HIV on the brain.

Early Brain Changes

Ann Regin of Northwestern University in Chicago (abstract 55LB) presented results from the a study of the Chicago Early HIV Cohort Study, titled "Injury to the Brain Evident in Early HIV Infection."

This study followed 43 people living with HIV for less than 1 year and compared them to 22 uninfected individuals. Researchers looked at high-resolution images of the brain and measured gray matter volume in a number of brain regions.

Results

	Total gray matter volume was lower among people living with HIV than among uninfected people; this was true in both cortical and sub-cortical regions.
	Significant changes were evident in people infected for less than 6 months, and changes were seen in some people as early as 2 months.
	Overall, these changes were subtle, but the Regin speculated that they might progress over time.
	Preliminary results suggest people on antiretroviral therapy (ART) experienced lesser brain changes.

This study comparing brain structure of people newly infected with HIV to uninfected individuals shows that HIV injures the brain in the earliest phases of infection. The preliminary results showing a lesser effect in people on HIV treatment bolster the argument for early initiation of ART.

Brain Injury and Inflammation

Branford Navia of Tufts University in Boston (abstract 56) presented results from the HIV Neuroimaging Consortium, titled "Neurologic Injury on Stable ART."

This study followed 167 people living with HIV over a 2-year period at 7 sites in the U.S. Researchers looked at changes in cognitive function and their relation to both HIV treatment and various measures of HIV infection

Results

	Declines in cognitive function increased by 13% after 1 year and 35% after 2 years.
	A CD4 count less than 350 cells/mm3 at the initiation of treatment was associated with increased risk of cognitive decline.
	Markers of increased inflammation were associated with decreased cognitive function.
	Age and length of time living with HIV were not associated with decline in cognitive function, however.
	Significant changes in brain structure were evident in people living with HIV.
	Low CD4 nadir (lowest ever count) was associated with a higher risk of brain injury.
	Progressive brain injury was associated with detectable HIV in the CSF, makers of immune activation, and time on ART.

This analysis shows that both neuropsychological function and brain structure are altered in people on stable antiretroviral treatment. Moreover, the risk of cognitive decline and brain injury were highest in people with the greatest level of immune deficiency and highest levels of inflammation and immune activation in the brain. Disappointingly, though, a greater amount of time on ART did not seem to reduce the risk of brain injury.

HIV Genetic Diversity

Finally, George Hightower of the University of California San Diego (abstract 57) presented results from the CHARTER Group, titled "Higher HIV Genetic Diversity is Associated with AIDS and Neuropsychological Impairment."

This study followed 187 people living with HIV, of whom 80 were men and almost 50% African American. Researchers measured levels of HIV genetic diversity and its effect on both rates of AIDS diagnosis and changes in neuropsychological impairment.

Results

	People with a high level of HIV genetic diversity in their plasma were 2.7 times more likely to have an AIDS diagnosis.
	Those with high rates of diversity in their CSF had similar (2.4 times) increases in rates of AIDS diagnoses.
	People with high rates of HIV genetic diversity in plasma or CSF or both also had nearly 2 times the amount of neuropsychological impairment.

This study suggests that a higher level of HIV genetic diversity is associated with an increased risk of both AIDS and neuropsychological impairment. Greater HIV genetic diversity has been associated with both longer length of time living with HIV and inversely with time on ART in other studies. These findings suggest that measuring HIV genetic diversity and strategies to reduce it might prove valuable in both predicting and intervening in neuropsychological impairment among people living with HIV.

Taken together, these studies present a sobering picture of the effects of HIV on brain function and structure. As people with HIV live longer, such effects become more important and research leading to a better understand of how to predict and affect HIV's impact on the brain become more crucial.

Investigator affiliations:

Abstract 54: Univ of California, San Francisco, CA; Univ of Hawaii, Honolulu, HI; Huntington Medical Research Inst, Pasadena, CA; South East Asia Research Collaboration with Hawaii and Thai Red Cross AIDS Research Ctr, Bangkok, Thailand; U.S. Military HIV Research Program, Walter Reed Army Inst of Research, Rockville, MD; Chulalongkorn Univ, Bangkok, Thailand; U.S. Armed Forces Research Inst of Medical Science, Bangkok, Thailand; HIVNAT Research Collaboration, Bangkok, Thailand.
Abstract 55: Northwestern Univ, Chicago, IL; NorthShore Univ Hosp, Evanston, IL; Children's Memorial Hosp, Chicago, IL.

Abstract 56: Tufts Univ School of Medicine, Boston, MA; Indiana Univ School of Medicine, Indianapolis, IN; Univ of Rochester School of Medicine, Rochester, NY; Univ of California, San Diego, CA; Univ of California, Los Angeles, CA; Univ of Colorado Denver, CO; Los Angeles Biomed Research Inst at Harbor-UCLA Medical Ctr, Torrance, CA; Brown Univ, Providence, RI.

Abstract 57: Univ of California, San Diego, CA; Univ of California, San Francisco, CA; San Francisco VAMC, San Francisco, CA; VA San Diego Healthcare System, San Diego, CA.

3/29/11

References

V Valcour, N Sailasuta, T Chalermchai, et al. HIV Brain Viral and Inflammatory Signature during Acute Infection. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 54.

A Rangin, Y Wu, H Du, et al. Injury to the Brain Is Evident Early in HIV Infection. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 55LB.

B Navia, J Harezlak, G Schifitto, et al. A Longitudinal Study of Neurological Injury in HIV-infected Subjects on Stable ART: The HIV Neuroimaging Consortium Cohort Study. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 56.

G Hightower, J Wong, S Letendre, et al. Higher HIV-1 Genetic Diversity Is Associated with AIDS and Neuropsychological Impairment. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 57.