Permitting us to survive and thrive in a sea of potentially infectious microbes, our immune systems are always at work. Laboring, for the most part, in relative silence and obscurity, these systems of defense may become compromised when Human Immunodeficiency Virus (HIV) threatens key CD4+ (T-helper) lymphocytes, integral to proper immune function.
Learning a bit about HIV and its lifecycle within infected CD4+ cells can help us to understand how medications used to treat infection with this virus work, and how regular quantitative monitoring of the virus (i.e., viral load) and immune system (i.e., CD4+ lymphocyte count) contribute to successful therapy.
Understanding these facts may also help to explain why taking antiviral medications regularly as directed is so critical to controlling HIV infection and its damaging effects on immunity.
Despite the many social, political, and economic dimensions that the pandemic of HIV infection may have assumed over the course of the past three decades, it is important to emphasize that HIV is after all, simply a virus. Viruses are relatively basic, sub-microscopic germs that are composed of genetic material bearing the code for their replication in the form of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), along with a number of critical viral proteins, generally surrounded by a protective envelope. Because viruses do not have all of the necessary tools to manufacture their own essential proteins, they must infect and act as parasites on the cells of a more complex living organism in order to reproduce.
HIV is an RNA virus that specifically targets human cells bearing a molecule known as CD4+ on their surfaces. Unfortunately, this targeted molecule, CD4+, is found on cells such as T-helper lymphocytes that are critical in orchestrating harmonious immunologic function.
Because they must transcribe their genetic code composed of RNA back into DNA copies within infected cells in order to effectively parasitize the host cells' machinery for creating protein (synthesis), viruses such as HIV are known as retroviruses.
In order to fully appreciate the impact of HIV upon CD4+ lymphocytes and the means by which antiviral medicines can decrease the negative results of this process, it is important to understand precisely how the virus attacks and replicates within infected cells.
HIV carries out its work of reproduction in a series of steps that, together, comprise the retroviral life cycle. These steps include: viral fusion with the cell membrane, reverse transcription, integration, transcription, translation, and viral assembly.
Each step offers opportunities for interruption of viral replication by means of molecules that specifically block the process at that particular stage. Medications used to treat HIV, known as antiretroviral therapy (ART), target specific stages in this lifecycle. When ART medications are used in combination, they are generally more effective at blocking the HIV lifecycle, sometimes at several distinct steps, while minimizing the risk of dose-related side effects of any one medicine used alone.
Another ART drug, which antagonizes the binding of HIV with CCR5 molecules, is known as maraviroc. Since not all HIV viruses utilize CCR5 to the same degree in viral fusion, a special viral blood test called a tropism or Trofile assay is generally performed prior to therapy with a CCR5 receptor antagonist in order to assess the likelihood that treatment with such medication will be effective in a given patient.
Upon viral fusion, HIV RNA and critical viral proteins, such as the enzyme reverse transcriptase, enter the host cell. Reverse transcriptase is responsible for catalyzing or facilitating the transcription of the viral RNA genetic code into DNA copies. This is critical for viral reproduction since the host cell's process for protein synthesis, which the virus must use for its own replication, begins with DNA (not RNA) in the cell nucleus.
Many ART medications work at blocking this step in the viral lifecycle. Among them are the nucleoside or nucleotide analogue reverse transcriptase inhibitors (NRTIs or "nukes"), such as zidovudine, didanosine, lamivudine, stavudine, abacavir, emtricitabine, and tenofovir, which are structurally similar to nucleosides or nucleotides that would ordinarily be incorporated into DNA copies by viral reverse transcriptase. The presence of these NRTIs instead thwarts the process of reverse transcription that is so vital to HIV reproduction. Other medications that are structurally different from nucleosides or nucleotides but also work by blocking reverse transcription are called non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs or "non-nukes"). Examples of NNRTIs are efavirenz, nevirapine, and etravirine.
Since reverse transcription is such a retrovirus-specific and critical step in the HIV lifecycle, medications that target this stage are often the backbone of ART combination regimens. Some frequently utilized combinations of NRTIs and NNRTIs have been co-formulated into combination pills that may facilitate adherence to therapy by limiting the number of pills that an HIV-positive patient takes each day. Examples include co-formulations of zidovudine with lamivudine; abacavir with lamivudine; zidovudine, abacavir, and lamivudine; tenofovir with emtricitabine; and tenofovir, emtricitabine, and efavirenz.
Once a newly formed viral DNA transcript has been produced, it must be integrated into the DNA of the human host cell nucleus in order to utilize that cell's ordinary process for protein synthesis. This step is catalyzed by the viral enzyme known as integrase. ART medications such as raltegravir are integrase inhibitors, and thereby interrupt the HIV lifecycle at this stage.
Having successfully integrated its DNA transcript into the host nuclear DNA, HIV next has its genetic code (now called proviral DNA) transcribed along with that of the host cell. The product of this transcription event is a new strand of RNA, known as messenger RNA (mRNA) because it is responsible for carrying the genetically encoded message, a blueprint for the formation of proteins, out of the cell nucleus and into the cytoplasm (the substance between the cell membrane and its nucleus), where the remainder of the process of protein synthesis occurs.
Once out in the host cell cytoplasm, the newly formed mRNA transcripts meet up with cytoplasmic structures known as ribosomes. Also composed of RNA, these ribosomes serve as sites where the mRNA-coded message is translated, permitting the appropriate alignment of specific amino acids, which are the fundamental building blocks of new viral proteins.
The new chains of amino acids thus formed must finally be cut into appropriately sized and structured protein pieces. This tailoring step, critical for the production of all of the enzymes and other proteins needed for the structure and repeated replication of HIV, is facilitated by the viral enzyme called protease.
Many powerful ART meds contain a class of molecules that block this enzyme. These drugs are known as protease inhibitors (PIs) and include: atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir.
Many times these medications are combined with another PI called ritonavir, which increases the bioavailability of the other co-administered PIs in the body by inhibiting a key enzyme system in the liver responsible for metabolizing or breaking down these PI molecules. Lopinavir is co-formulated with ritonavir in a single pill for this purpose.
The HIV Life Cycle
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By means of a very sensitive test called a polymerase chain reaction (PCR), it is possible to measure how many copies of HIV RNA may be found in the blood of an infected individual. The result of such a test is often referred to as a viral load, and is most frequently expressed as the number of copies of HIV RNA detected in a milliliter (ml) of plasma (the liquid component of blood). Though a number of different tests are in use to measure viral load with different lower limits of viral detection, all are generally very reliable.
When the number of copies of HIV RNA is lower than the lower limit of detection of the assay being used, the viral load is said to be undetectable.
An important goal of treatment for most patients receiving ART is to attain and maintain an undetectable viral load. This does not mean that HIV is eradicated from the treated person, but rather that viral replication has been controlled to the extent that the amount of virus present in the blood is below the lower limit of detection of the viral load test.
Thus, it is important to perform viral load testing at baseline (i.e., prior to starting any new ART) and generally at 4- to 12-week intervals thereafter, depending upon response to treatment. For example, an HIV-positive individual who is feeling well, tolerating and adhering to medications well, and has had consistently undetectable viral loads and healthy CD4+ cell counts may only require such viral load testing every three to six months; whereas, someone who is symptomatic, having difficulty with tolerating or adhering to ART, or has had prior high or increasing viral loads or low CD4+ counts may require more frequent monitoring.
When possible, achieving an undetectable HIV viral load on ART may take weeks to months. Once attained, however, it requires (at least at this time), a lifetime of regular adherence to prescribed ART to maintain. Maintaining an undetectable viral load indicates that the HIV lifecycle is being suppressed to the extent possible within a given person. This minimizes the risk that the virus will develop mutations (i.e., mistakes in genetic coding) that are associated with resistance to ART.
Replicating up to billions of times daily within an infected person, particularly in the absence of completely suppressive ART (such as when treatment adherence has been lax), mistakes or mutations in the HIV genetic code may occur frequently.
Such mutations, when conferring resistance to a particular ART drug or class of drugs, may provide the mutant virus with a selective survival advantage in the accelerated evolutionary scheme of the microbial environment within an infected individual. Mutant HIV may then become predominant, rendering treatment with that particular ART drug, or in some cases, class of ART drugs, ineffective for that person.
Thus, when viral loads are noted to be consistently elevated, it is appropriate to perform blood tests called HIV genotype or phenotype in order to determine whether resistance mutations have emerged, and to what extent existing mutations may create resistance to available ART agents.
Such testing may also help treating clinicians to determine whether a change in ART may be helpful in suppressing the HIV lifecycle, and to what extent it might be possible to expect favorable viral load suppression with each of the available ART medications and combinations. This may greatly facilitate selection of a new ART regimen if that is necessary in order to establish or reestablish viral load suppression and so reduce the risk of HIV-related injury to CD4+ cells, which are so pivotal to the proper functioning of the immune system.
A target of HIV, the CD4+ lymphocyte plays a central role in the immune system, which has been likened to that of the conductor of an orchestra. Performing appropriately and in adequate numbers, the CD4+ cell directs the immune system's harmonious functioning, defending the body from harmful invading microbes or malignant neoplastic (abnormal or tumorous) cells without injury to healthy tissues. However, a decline in CD4+ number can permit a cacophony of serious opportunistic infections (OIs) such as Pneumocystis pneumonia (PCP); cytomegalovirus (CMV); toxoplasmosis; malignancies (for example, lymphoma or Kaposi sarcoma); or autoimmune disorders, wherein the immune system injures normal cells, as in idiopathic thrombocytopenic purpura (ITP).
Disturbingly, HIV may attach itself to CD4+ molecules, gaining entry to, parasitizing, and destroying these critical immune cells in large numbers for long periods of time while the infected individual may remain free of symptoms. This is because the body continues to produce large numbers of CD4+ cells in an effort to replace those lost.
At this point, an HIV-positive individual may be described as having Acquired Immunodeficiency Syndrome (AIDS).
Therefore, an important goal of therapy for HIV infection is to attain and maintain healthy CD4+ lymphocyte (T-cell) numbers. These may be measured with a special blood test known as the CD4+ lymphocyte count, which is performed upon diagnosis of HIV infection to assess the potential benefit of immediate versus deferred ART and/or prophylactic medication to prevent certain OIs. This test will be repeated at intervals thereafter to reassess the need for beginning ART in untreated individuals, and to monitor treatment response in those receiving ART.
Currently, ART is generally recommended for people living with HIV when they have symptoms related to their infection, or if asymptomatic, when they have CD4+ counts at or below 350 cells/mm3. Medical knowledge about HIV, ART, and the immune system continues to grow as do new treatment options; and so, guidelines for precisely when to begin ART also continue to evolve.
Guidelines for the prevention of OIs in HIV-positive patients also provide specific recommendations for when to begin prophylactic, or preventative, medications. For those individuals who have not experienced symptoms of a particular OI, the threshold for beginning such prophylaxis is based upon CD4+ cell count (as when trimethoprim/sulfamethoxazole [Bactrim] for PCP prevention is recommended at 200 cells/mm3).
Conversely, individuals treated with ART who experience a rise in CD4+ counts following control of HIV replication that is sustained over several months may receive a recommendation to discontinue certain prophylactic medications for OIs.
Therefore, CD4+ lymphocyte numbers may be measured every three to six months in asymptomatic HIV-infected persons with relatively high counts who are either not taking ART or are stable on ART, while these tests may be performed more frequently when deciding upon the need to initiate ART or OI prophylaxis, when symptoms develop, or when CD4+ decline accelerates.
Currently available ART regimens cannot eradicate HIV infection even when used as directed, since integrated provirus can remain for prolonged periods within human cells. Lapses in ART can result in continuation of the HIV lifecycle with renewed viral replication. This can lead to increases in measured viral load and subsequent reductions in CD4+ lymphocyte counts, with increased risk of disease progression to AIDS and of more serious opportunistic illnesses.
Learning about HIV and its lifecycle within host CD4+ cells provides us with an enhanced appreciation for the dynamics of ART treatment and for why adherence to such therapy can be so vital to the integrity of immune defenses. Sharing such an appreciation, health care providers and patients can form powerful therapeutic alliances, keeping HIV infection at bay.
It is important that infected individuals identify, and actively engage with, knowledgeable and interested caregivers who are open to questions and frank discussions about HIV and related issues, including experiences with side effects of medications. Although current ART cannot cure HIV infection, it can be an integral and empowering element of care aimed at enjoying a longer and healthier life.
Joseph S. Cervia, M.D., M.B.A., FACP, FAAP, FIDSA, AAHIVS is currently Clinical Professor of Medicine and Pediatrics at the Albert Einstein College of Medicine in New York, Volunteer Attending Physician at the Center for AIDS Research and Treatment of the North Shore/Long Island Jewish Health Network, and Medical Director and Senior Vice President for Pall Corporation. A board-certified internist, pediatrician, adult and pediatric infectious diseases, and HIV medicine specialist, Dr. Cervia has dedicated much of his career to the care of individuals and families battling HIV and other infectious diseases, and to clinical research related to prevention, therapeutics, complicating illnesses, and quality of life issues. He has authored over 100 articles, chapters, and abstracts, lectured widely, and serves as a consultant to numerous local, national, and international organizations on HIV and infectious disease-related issues.
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