The male genital tract is not a sanctuary site for HIV, argue Dutch researchers

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A group of Dutch researchers have argued that the male genital tract is not an important site for the production of drug-resistant strains of HIV. They suggest that the HIV found in semen does not originate from cells in the semen (which contains low levels of antiretroviral drugs), but from the blood or the lining of the genital tract (which are exposed to therapeutic levels of the drugs). The article is presented in the July 2nd edition of AIDS.

The male genital tract is generally considered to be a ‘sanctuary site’ for HIV due to the presence of the blood-testis barrier, a layer of cells connected by specialised ‘tight junctions’ that prevent drugs from passing between the blood and the areas of the testis where sperms develop and mature. This, according to current thinking, is the cause of low levels of antiretroviral drugs in semen, which is in turn thought to allow the selection and development of HIV strains that are resistant to the drugs.

Arguments against the importance of the blood-testis barrier

Glossary

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

strain

A variant characterised by a specific genotype.

 

protein

A substance which forms the structure of most cells and enzymes.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

In their article, the authors, from the University of Amsterdam, refute the current theory on the basis of anatomical, virological and immunological observations. Although the blood-testis barrier does prevent antiretroviral drugs from entering the semen, it only protects a small fraction of the genital tract within the seminiferous tubules, where the sperm cells develop. Additionally, 90% of the fluid produced in the tubules is absorbed again in the epididymis, where the sperms are stored before ejaculation.

Although antiretroviral drugs could diffuse from the blood to the semen in the regions of the genital tract not protected by the blood-testis barrier, the authors argue that they are prevented from doing so by being tightly bound to protein molecules in the blood. They observe that antiretroviral drugs that bind to protein with an affinity of less than 90% reach “moderate to good” concentrations in the semen. Most antiretrovirals, with the exception of nucleoside analogues, have protein affinities of over 90%, leading to low drug levels in the semen.

“Therefore the blood-testis barrier is not an explanation for the subtherapeutic drug concentrations in the seminal plasma,” the authors argue.

Arguments against the production of drug-resistant virus in the semen

The authors point out that CD4 T-cells are not found in the fluid surrounding the developing sperms. Therefore, although HIV can enter the semen from the blood at various points along the genital tract, the virus is left with nowhere to replicate.

Furthermore, semen has low levels of immunological activity, in order to protect the sperm cells from being destroyed by the immune system. The absence of immune cell activation prevents HIV replication and the production of drug-resistant strains, even in the presence of low antiretroviral drug concentrations.

“Antiretroviral drug concentrations ‘behind’ the blood-testis barrier are not relevant,” suggest the authors, “and as a consequence the lumen of the seminiferous tubules normally cannot be a sanctuary site for HIV.”

Their hypothesis is supported by a number of observations from the medical literature. Firstly, they note that vasectomy does not decrease the concentration of HIV in the semen, suggesting that the majority of the HIV does not originate from the testes, but from the seminal vesicles or the prostate gland, which provide over 80% of the volume of semen.

Additionally, most patients taking antiretroviral therapy show parallel viral load reductions in the blood and in the semen. Resistance mutations are also rarely found in HIV from the semen before they are found in the blood, suggesting that seminal HIV probably originates from cells in the blood or the genital tract lining, but that further HIV replication is suppressed in the seminal fluid.

Dr Tariq Sadiq, Senior Lecturer and Honorary Consultant in HIV and genitourinary medicine at St. George's Hospital Medical School, told aidsmap.com that "the authors of this article are right to challenge the assumption that semen reflects biological events in the male genital tract."

"Many studies have shown that patients on protease inhibitor- or efavirenz-containing regimes have suppressed semen viral loads although there is poor penetration of these drugs into semen. This is probably because penetration [of these drugs] into the tissues of the genital tract, where it is likely to matter most, is not poor," he continued. "However, another explanation is that the nucleoside analogue components of the regimens, which are often at high levels in the semen, may be adequate to suppress genital tract virus."

A role for inflammation?

The authors of the article acknowledge that HIV replication could occur under circumstances of inflammation or infection in the genital tract, when leukocytes may be present in the semen. They suggest that the presence of a sexually transmitted infection could underlie this, potentially leading to the production of drug-resistant virus.

“The treatment of local inflammation/infection could be an important measure for preventing the development and transmission through semen of drug-resistant virus. This warrants the aggressive screening for and treatment of sexually transmitted infections and local inflammation in such patients.”

However, Dr Sadiq pointed out that "the role of genital inflammation may not necessarily be critical. In the work we have done in the UK, a minority of men negative for urethritis and sexually transmitted infections had viral loads considerably higher in semen compared to blood.

"So although it is true that the role of the genital tract as a separate compartment is often exaggerated, more work needs to be done to investigate non-inflammatory factors associated with apparent 'independent' genital HIV-1 replication."

Further information on this website

Treating HIV in the genital tract

Resistance - factsheet

Resistance - patient information booklet

Gonorrhoea is STI most likely to cause HIV rebound in semen of HAART patients - news article

Reference

Lowe S H et al. Is the male genital tract really a sanctuary site for HIV? Arguments that it is not. AIDS 18: 1353-1362, 2004.