Antiherpes antivirals direclty inhibit HIV

[Guest guest]

that is not through lowering overall viral load and freeing the immune

system, but through DIRECT inhibition of HIV virus (even though it is

not supposed to, it is a different type of virus, but heaps of studies

showing exactly that).

makes me wonder if all we doing right now in autism treatments is

blindfold fighting a HIV-like virus?

or has HIV mutated as to not be deadly to humans any more (as in simian

immunodeficiency virus, which is only deadly in some monkeys, and

relatively harmless in others)? and has tricked our immune systems into

not producing antibodies - meaning it would be impossible to detect by

standard ELISA hiv test ???

does drG have an opinion on retroviruses in autism? is he testing for

any?

J Biol Chem. 2008 Nov 14;283(46):31289-93. Epub 2008 Sep 24.

The antiherpetic drug acyclovir inhibits HIV replication and selects the

V75I reverse transcriptase multidrug resistance mutation.

McMahon MA

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22M\

cMahon%20MA%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Res\

ultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus> et al.

Department of Pharmacology and Molecular Sciences, s Hopkins

University School of Medicine, Baltimore, land 21205, USA.

The antiviral drug acyclovir is a guanosine nucleoside analog that

potently inhibits herpes simplex virus (HSV) replication. Acyclovir

treatment in patients coinfected with HSV and human immunodeficiency

virus (HIV) has been observed to alter disease course and decrease HIV

viral load, a finding that has been attributed to indirect effects of

HSV suppression on HIV replication. Based on this hypothesis, several

clinical studies have recently investigated the use of acyclovir for

treatment of patients coinfected with HSV and HIV or for prophylaxis

against HIV transmission. In this report, we use a single round HIV

infectivity assay to show that acyclovir directly inhibits HIV infection

with an IC50 of approximately 5 microm. The target of acyclovir in

HIV-infected cells is validated as HIV reverse transcriptase (RT) by the

emergence of the RT variant V75I under the selective pressure of

acyclovir. The V75I mutation is part of the multidrug resistance pathway

that enhances viral resistance to many of the best RT inhibitors

approved for the treatment of HIV. Biochemical analyses demonstrate that

acyclovir triphosphate is a chain terminator substrate for HIV RT and

can compete with dGTP for incorporation into DNA. Although acyclovir may

prove a useful lead for development of new HIV treatments, the selection

of resistant mutants raises a cautionary note to the use of acyclovir

monotherapy in patients coinfected with HSV and HIV. PMID: 18818198

Cell Host Microbe. 2008 Sep 11;4(3):260-70.

Comment in:

Cell Host Microbe. 2008 Sep 11;4(3):194-5.

<http://www.ncbi.nlm.nih.gov/pubmed/18779044?ordinalpos=1 & itool=EntrezSy\

stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RV\

AbstractPlus>

Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in

herpesvirus-infected human tissues.

Lisco A

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22L\

isco%20A%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Result\

sPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus> , et al.Eunice

Kennedy Shriver National Institute of Child Health and Human

Development, National Institutes of Health, Bethesda, MD 20892, USA.

For most viruses, there is a need for antimicrobials that target unique

viral molecular properties. Acyclovir (ACV) is one such drug. It is

activated into a human herpesvirus (HHV) DNA polymerase inhibitor

exclusively by HHV kinases and, thus, does not suppress other viruses.

Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues,

but not in HHV-free tissue or cell cultures. However, addition of

HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV

activity. We hypothesized that such HIV suppression requires ACV

phosphorylation by HHV kinases. Indeed, an ACV monophosphorylated

prodrug bypasses the HHV requirement for HIV suppression. Furthermore,

phosphorylated ACV directly inhibits HIV-1 reverse transcriptase (RT),

terminating DNA chain elongation, and can trap RT at the termination

site. These data suggest that ACV anti-HIV-1 activity may contribute to

the response of HIV/HHV-coinfected patients to ACV treatment and could

guide strategies for the development of new HIV-1 RT inhibitors.PMID:

18779052

J Infect Dis. 2008 Dec 15;198(12):1804-8.

Herpes simplex virus (HSV)-suppressive therapy decreases plasma and

genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized,

placebo-controlled, cross-over trial.

Baeten JM

<http://www.ncbi.nlm.nih.gov/sites/?Db=pubmed & Cmd=Search & Term=%22Baeten%\

20JM%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPan\

el.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus> ,et al.Department of

Global Health, University of Washington, Seattle, WA 98104, USA.

jbaeten@...

<../../../../new-a-p/post?postID=AIC3cCoGo1hjbrE7bDNH5NSifC33yNVcLDKedW-\

AzmTcZPizzPNmViQyYSwLp3-X4BC4x_aguXqcY-AYaefCycs>

A randomized cross-over trial of herpes simplex virus type 2

(HSV-2)-suppressive therapy (valacyclovir, 500 mg twice daily, or

placebo for 8 weeks, a 2-week washout period, then the alternative

therapy for 8 weeks) was conducted among 20 Peruvian women coinfected

with HSV-2 and human immunodeficiency virus type 1 (HIV-1) who were not

on antiretroviral therapy. Plasma samples (obtained weekly) and

endocervical swab specimens (obtained thrice weekly) were collected for

HIV-1 RNA polymerase chain reaction. Plasma HIV-1 level was

significantly lower during the valacyclovir arm, compared with the

placebo arm (-0.26 log10 copies/mL, a 45% decrease [P < .001]), as was

cervical HIV-1 level (-0.35 log10 copies/swab, a 55% decrease [P <

..001]). Suppressive HSV-2 therapy has the potential to reduce HIV-1

infectiousness and slow HIV-1 disease progression.MID: 18928378

J Infect Dis. 2007 Nov 15;196(10):1500-8. Epub 2007 Oct 31.

Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal

and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a

randomized, double-blind, placebo-controlled crossover trial.

Zuckerman RA

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Z\

uckerman%20RA%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R\

esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus> , et al Section

of Infectious Disease and International Health, Dartmouth-Hitchcock

Medical Center, Lebanon, NH, USA. ccelum@...

BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection is common

among human immunodeficiency virus (HIV)-infected persons, and HSV

reactivation increases plasma and genital HIV-1 levels. We studied HIV-1

levels during HSV suppression in coinfected persons in a

placebo-controlled crossover trial. METHODS: Twenty antiretroviral

therapy (ART)-naive HIV-1/HSV-2-seropositive men who have sex with men

in Lima, Peru, with CD4 cell counts >200 cells/ microL were randomized

to receive either valacyclovir at 500 mg twice daily or placebo for 8

weeks, after which they underwent a 2-week washout period and then

received the alternative regimen for 8 weeks. Specimens included daily

anogenital swabs (for HSV DNA polymerase chain reaction [PCR]), thrice

weekly rectal mucosal secretions (for HIV-1 RNA and HSV DNA PCR)

obtained by anoscopy, and weekly plasma (for HIV-1 RNA PCR). Outcomes

were rectal and plasma HIV-1 RNA levels by treatment arm. RESULTS: HIV-1

was detected in 73% of 844 rectal and 99% of 288 plasma specimens. HSV

was detected in 29% and 4% of mucocutaneous specimens obtained during

placebo and valacyclovir administration, respectively (P<.001).

Valacyclovir resulted in a 0.16 (95% confidence interval [CI],

0.07-0.25; P=.0008; 33% decrease) log(10) copies/mL lower mean

within-subject rectal HIV-1 level and a 0.33 (95% CI, 0.23-0.42;

P<.0001; 53% decrease) log(10) copies/mL lower plasma HIV-1 level,

compared with values for placebo. CONCLUSIONS: Valacyclovir

significantly reduces rectal and plasma HIV-1 levels in

HIV-1/HSV-2-coinfected men. HSV suppression may provide clinical

benefits to persons not receiving highly active ART as well as public

health benefits.PMID: 18008230

J Infect Dis. 2008 Dec 15;198(12):1804-8.

Herpes simplex virus (HSV)-suppressive therapy decreases plasma and

genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized,

placebo-controlled, cross-over trial.

Baeten JM

<http://www.ncbi.nlm.nih.gov/sites/?Db=pubmed & Cmd=Search & Term=%22Baeten%\

20JM%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPan\

el.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus> , et al

Department of Global Health, University of Washington, Seattle, WA

98104, USA. jbaeten@...

<../../../../new-a-p/post?postID=-eBCVrwmicLNB5vKExdikqD-6Xberfqxnvi3mRc\

MgsYpwAnTL3z72b5TNDTtzC2ux3KhS7X_XUufMYDDTnS5T8UO>

A randomized cross-over trial of herpes simplex virus type 2

(HSV-2)-suppressive therapy (valacyclovir, 500 mg twice daily, or

placebo for 8 weeks, a 2-week washout period, then the alternative

therapy for 8 weeks) was conducted among 20 Peruvian women coinfected

with HSV-2 and human immunodeficiency virus type 1 (HIV-1) who were not

on antiretroviral therapy. Plasma samples (obtained weekly) and

endocervical swab specimens (obtained thrice weekly) were collected for

HIV-1 RNA polymerase chain reaction. Plasma HIV-1 level was

significantly lower during the valacyclovir arm, compared with the

placebo arm (-0.26 log10 copies/mL, a 45% decrease [P < .001]), as was

cervical HIV-1 level (-0.35 log10 copies/swab, a 55% decrease [P <

..001]). Suppressive HSV-2 therapy has the potential to reduce HIV-1

infectiousness and slow HIV-1 disease progression. PMID: 18928378

J Acquir Immune Defic Syndr. 2004 Apr 15;35(5):435-45.

The effects of herpes simplex virus-2 on HIV-1 acquisition and

transmission: a review of two overlapping epidemics.

Corey L

<http://www.ncbi.nlm.nih.gov/sites/?Db=pubmed & Cmd=Search & Term=%22Corey%2\

0L%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel\

..Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus> , et al Department of

Medicine, University of Washington Program in Infectious Diseases, Fred

Hutchinson Cancer Research Center, Seattle, WA 98109, USA. lcorey@...

Increasing evidence demonstrates a substantial link between the

epidemics of sexually transmitted HIV-1 and herpes simplex virus (HSV)-2

infection. More than 30 epidemiologic studies have demonstrated that

prevalent HSV-2 is associated with a 2- to 4-fold increased risk of

HIV-1 acquisition. Per-sexual contact transmission rates among couples

from Rakai, Uganda indicate that at all levels of plasma HIV-1 RNA in

the source partner, HSV-2-seropositive HIV-1-susceptible persons have a

5-fold greater risk of acquiring HIV-1 compared with HSV-2-negative

persons. In vitro and in vivo studies suggest that mucosal HIV-1

shedding is more frequent and in greater amounts during mucocutaneous

HSV-2 replication, including subclinical mucosal reactivations. Most

HIV-1-infected persons are coinfected with HSV-2, and most experience

frequent subclinical and clinical reactivations of HSV-2. Subclinical

HSV reactivation elevates serum HIV-1 RNA levels, and daily therapy with

acyclovir appears to reduce plasma HIV-1 RNA. These data show that

greater attention to the diagnosis and treatment of HSV-2 among

HIV-1-infected persons is warranted, especially those who continue to be

sexually active, those not on antiretroviral therapy, or those whose

disease is not well suppressed by antiretrovirals. PMID: 15021308

J Infect Dis. 2002 Dec 15;186(12):1718-25. Epub 2002 Nov 22.

Changes in plasma human immunodeficiency virus type 1 RNA associated

with herpes simplex virus reactivation and suppression.

Schacker T

<http://www.ncbi.nlm.nih.gov/sites/?Db=pubmed & Cmd=Search & Term=%22Schacke\

r%20T%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPa\

nel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus> , Department of

Medicine, University of Minnesota, Minneapolis, 55455, USA. Schac008@...

In early trials of antiretroviral therapy, acyclovir was associated with

increased survival by an unknown mechanism. The hypothesis that

subclinical herpes simplex virus (HSV) reactivation was associated, in

vivo, with increased plasma human immunodeficiency virus (HIV) RNA and

suppression with a reduced plasma HIV RNA load was investigated. HSV

cultures were performed daily on HSV-2-positive/HIV-positive patients,

and plasma HIV-1 RNA loads were measured at regular intervals. A subset

of patients prior to, during, and after HSV suppression with high-dose

acyclovir was measured to determine whether HSV suppression was

associated with a decrease in HIV replication. Most (25/27

HSV-2-positive/HIV-positive persons) reactivated HSV. Total HSV shedding

rate was strongly correlated with plasma HIV-1 RNA load (R=0.54;

P=.004), and the plasma HIV-1 RNA level at a given CD4 cell count was

48% lower when treated with acyclovir. These data indicate that frequent

mucosal HSV reactivation influences HIV replication in vivo and daily

HSV suppression may be important in the management of

HSV-positive/HIV-positive persons. PMID: 12447756