[Viva] FW: CATIE News - Does syphilis affect HIV in the brain?

[Tami]

From: mailing at mercury.catie.ca [mailto:mailing at mercury.catie.ca] 
Sent: February-01-11 2:06 PM
To: cosmictami at shaw.ca
Subject: CATIE News - Does syphilis affect HIV in the brain?

 

CATIE News - Does syphilis affect HIV in the brain?

Outbreaks of sexually transmitted infections (STIs) are occurring in Canada
and other high-income countries. STIs can cause inflammation, sores, ulcers
or lesions on or inside delicate ano-genital tissues. In addition to the
specific damage that each STI causes, the inflammation and sores caused by
STIs can provide a portal for HIV and other germs to be transmitted.

 

Researchers have noted several similarities between syphilis and HIV,
including the following: 

*	Co-infection with syphilis and HIV is relatively common because both
microbes are sexually transmitted. 

*	The germs that cause syphilis (called treponemes or spirochetes) can
invade and replicate inside the brain and spinal cord (the central nervous
system, or CNS) shortly after they invade the body. HIV also enters the CNS
shortly after infection and replicates inside cells of the immune system
that are in the CNS. 

Syphilis is particularly problematic because it can damage such organs as
the heart, kidney, liver, eyes and brain. There are reports of increased
rates of syphilis among some men who have sex with men, some of whom are
also HIV-positive.

 

Researchers at the University of California at San Diego, a centre for
excellence in neuroAIDS research, are concerned about the impact of both HIV
and syphilis on the brain. This concern arises in part because HIV infection
is generally associated with an increased risk for neurocognitive
impairment. A large study has found that such impairment can persist despite
the use of potent anti-HIV therapy, commonly called ART or HAART.

 

If treponemes invade the CNS, there is the possibility that they might
increase inflammation. This, in turn, can increase the production of HIV and
its proteins, which are toxic for brain cells. Ultimately, if such effects
persist, there is the possibility that they could slowly degrade the brain,
amplifying the possibility of neurocognitive decline.

 

The San Diego team has found that HIV-positive people with neurosyphilis had
higher levels of HIV replication in the brain than other HIV-positive people
without neurosyphilis. The possible reasons for these findings and their
implications are explored in this report.

 

Study details

Researchers collected extensive health data from 225 HIV-positive
participants who were being monitored as part of a larger long-term study.
All participants received extensive neurological, psychiatric and medical
assessments.

 

With regard to syphilis, participants' blood samples were first screened for
antibodies suggestive of having syphilis, and positive results were
confirmed with other tests. Similar testing was done on cerebrospinal fluid
(CSF), in which the brain and spinal cord float.

 

The basic profile of participants was as follows: 

*	age - 40 years
*	1% females, 99% males
*	current CD4+ count - 357 cells
*	nadir (lowest-ever) CD4+ count - 191 cells
*	viral load in the blood - 1,600 copies/ml
*	60% of participants were taking HAART 

In summary, study volunteers were mostly men around the age of 40 with a
history of immune deficiency.

 

Results

Based on the reports from laboratory testing, researchers divided
participants into three groups as follows: 

*	23 people with neurosyphilis
*	42 people with systemic syphilis who did not have neurosyphilis
*	160 people who tested negative for syphilis 

Participants who tested positive for syphilis were asked for permission to
contact their family doctor so that treatment for syphilis could be
coordinated.

 

Syphilis before neurosyphilis 

Most participants who had neurosyphilis reported that they had been
diagnosed with and treated for syphilis in the past. According to the
research team, this previous treatment for syphilis had been "appropriate";
however, details about specific treatment were not published.

 

Viral load in the blood and CSF

CSF viral load was greatest in people classified as having neurosyphilis,
followed by people classified as having systemic syphilis, followed by
people classified as not having syphilis.

 

Researchers did analyses of the anti-HIV regimens that all three groups of
participants took but found that there were no significant differences
between the regimens and their ability to penetrate the brain. Further
analysis that took many factors into account-a multivariate analysis-found
that the effects of neurosyphilis and syphilis on viral load in the CSF were
not affected by viral load in the blood.

 

Putting together the puzzle

Based on the data gathered, the research team suggests that syphilis
co-infection may increase viral load in the CSF. However, researchers were
intrigued by their findings because none of the participants classified as
having neurosyphilis appeared to have signs/symptoms suggestive of active
neurosyphilis and their prior treatment for syphilis was considered
"appropriate."

 

Moreover, routine laboratory tests used to assess the severity of
neurosyphilis did not suggest rampant infection in the CNS.

 

The researchers note that both treponemes and HIV affect sentinel cells of
the immune system called macrophages. These cells alert the immune system to
the presence of invading germs. Macrophages can do so because that is one of
their major roles. Activated macrophages release chemical messengers called
cytokines that help activate and inflame the local immune system in the CNS
so that it can better identify and control invading germs.

 

The San Diego team suggests that the immune system in the CNS of some
HIV-positive people who have had syphilis or neurosyphilis appears to become
permanently activated. This activation has an inadvertent effect of making
immune system cells susceptible to HIV infection. As these cells become
infected with HIV, they are transformed into miniature virus factories,
spewing out more copies of HIV, raising viral load and releasing proteins
that are toxic to brain cells.

 

The researchers also note that ongoing immune activation (triggered by
syphilis) in the brains of HIV-positive people could "predispose them to a
higher frequency of neurocognitive impairment." Although neurocognitive
impairment was not assessed in the present study, a previous study also
conducted at the University of California at San Diego in the mid-1990s
assessed and compared neurocognitive impairment in 453 HIV-positive and 219
HIV-negative volunteers who had a history of syphilis or gonorrhea.
Researchers found that participants who were HIV positive and who had a
history of syphilis or gonorrhea tended to have neurocognitive deficits
compared to HIV-negative people with syphilis or gonorrhea. This difference
occurred regardless of education level and anti-HIV drugs and was present
even though participants had modest CD4+ cell counts (460 cells).

 

Other studies in the present era have found that systemic syphilis can
reduce the CD4+ counts of HIV-positive people. However, once syphilis is
treated, CD4+ counts return to their pre-syphilis levels.

 

Taken together, the two neurology studies done at the University of
California at San Diego raise the possibility that even after syphilis has
been treated appropriately it may adversely affect the immune system in
subtle ways-such as causing immune activation in the CNS.

 

Immune activation is not a trivial problem; it appears to play a role in
many of the complications that are appearing in HIV-positive people, even
those whose infections are under control with ART.

 

The present study was retrospective in design. Such studies can
inadvertently cause biased interpretation of data. The San Diego team took
pains to reduce the possibility of inadvertent bias, however, this problem
cannot entirely be ruled out. Based on the results of the present study, the
San Diego team suggests that future studies are necessary to assess whether
co-infection with HIV and syphilis is indeed linked to greater rates of
neurocognitive impairment. Hopefully such studies will include high-tech
tests such as PCR and other assessments for treponemes in the brain.

 

Acknowledgement

We thank Ronald Ellis, MD, PhD, University of California at San Diego, for
expert review. 

 
-Sean R. Hosein

REFERENCES: 

1.     Fang L, Oliver A, Jayaraman G, Wong T, et al. Trends in age
disparities between younger and middle-age adults among reported rates of
Chlamydia, gonorrhea, and infectious syphilis infections in Canada: Findings
from 1997 to 2007. Sexually Transmitted Infections. 2010 Jan;37(1):18-25. 

2.     van de Laar MJ. HIV/AIDS and other STIs in men who have sex with
men-a continuous challenge for public health. Eurosurveillance. 2009 Nov
26;14(47). pii: 19423. 

3.     Savage EJ, Hughes G, Ison C, et al. Syphilis and gonorrhoea in men
who have sex with men: a European overview. Eurosurveillance. 2009 Nov
26;14(47). pii: 19417. 

4.     Sullivan PS, Hamouda O, Delpech V, et al. Reemergence of the HIV
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5.     Zablotska IB, Imrie J, Prestage G, et al. Gay men's current practice
of HIV seroconcordant unprotected anal intercourse: serosorting or
seroguessing? AIDS Care. 2009 Apr;21(4):501-10. 

6.     Lukehart SA, Hook EW 3rd, Baker-Zander SA, et al. Invasion of the
central nervous system by Treponema pallidum: implications for diagnosis and
treatment. Annals of Internal Medicine 1988 Dec 1;109(11):855-862. 

7.     Tramont EC. Treponema pallidum (syphilis). In: Mandell GL, Bennett JE
and Dolin R, editors. Principles and Practice of Infectious Diseases. Sixth
ed. Philadelphia: Elsevier; 2005. P. 2362-2379. 

8.     Lukehart SA. Syphilis. In: Fauci AS, Braunwald E, Kasper DL, editors.
Harrison's Principles of Internal Medicine. 17th ed. McGraw-Hill Companies,
Inc.; 2008. P. 956-962. 

9.     Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated
neurocognitive disorders before and during the era of combination
antiretroviral therapy: differences in rates, nature, and predictors.
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10.  Heaton RK, Clifford DB, Franklin DR Jr., et al. HIV-associated
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11.  de Almeida SM, Bhatt A, Riggs PK, et al. Cerebrospinal fluid human
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12.  Wallace MR, Heaton RK, McCutchan JA, et al. Neurocognitive impairment
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13.  Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid
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14.  Marra CM, Tantalo LC, Sahi SK, et al. CXCL13 as a cerebrospinal fluid
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15.  Champion CI, Blanco DR, Lovett MA. Quantitative assessment of
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16.  Deeks SG. HIV infection, inflammation, immunosenecence and aging.
Annual Review of Medicine. 2011 Feb 18;62:141-55.

 

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