Cellular Automata Simulation of Interrupted Plasma Aphaeresis on AIDS Patients: Investigating Effects of Different Clearance Rate

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1 Cellular Auomaa Simulaion of Inerruped lasma Aphaeresis on AIDS aiens: Invesigaing Effecs of Differen Clearance Rae Sompop Moonchai, Yongwimon enbury Absrac The use of a combinaion of hree or more anireroviral drugs, called he Highly Acive Anireroviral Therapy (HAART), has been found o keep he viral load of HIV in he paien's body a a conrollable level as well as improve he immune sysem. However, if HAART is abandoned, a rebound of plasma viral load occurs which led us o believe ha he use of his reamen is associaed wih meabolic side effecs in human, including increased risk for opporunisic infecions. In order o avoid he problems wih drug reamen, an alernaive reamen by Aphaeresis has been suggesed. In plasma aphaeresis, he virus in he large molecular componens of plasma are removed from a paien afer which he small molecular componens of plasma and cell componens of blood are reurned o he paien. Several sudies seem o sugges ha plasma aphaeresis could be a good reamen for AIDS paiens wih peripheral polyneuropahy since plasma pheresis has been found o be capable of reducing a paien s plasma viral load o half of he original load. In his paper, we modify he CA rules based on he CA model of Moonchai and enbury [] o invesigae he acion of plasma aphaeresis herapy on he CD+ T cells and viral load in boh he lymph node and blood comparmens. Effecs of differen clearance raes of plasma aphaeresis herapy are invesigaed. Keywords Human immunodeficiency virus, HIV infecion, Cellular Auomaa, plasmapheresis reamen. I. INTRODUCTION OMUTER simulaion modeling has become increasingly C imporan in decision making in modern medicine. Admiedly, clinical sudies, in paricular large-scale randomized conrolled rials, remain he main source of informaion for decision makers. However, modeling is gaining accepance as a valuable ool o provide informaion on long-erm medical and socio-economical oucomes. Compuer simulaion models can provide informaion for healh care decision makers and allow hem o make he mos S. Moonchai is wih he Deparmen of Mahemaics, Faculy of Science, Chiengmai Universiy, Chiengmai, and he Cenre of Excellence in Mahemaics, THAIAND ( umah@gmail.com). Y. enbury is wih he Deparmen of Mahemaics, Faculy of Science, Mahidol Universiy, Rama Road, angkok, and he Cenre of Excellence in Mahemaics, Thailand (corresponding auhor, phone: --5; fax: --533; scylb@yahoo.com). informed choices beween available reamens proocols. For such reasons, he healh care indusry is relying more and more on modeling o make well informed decisions. Acquired Immune Deficiency Syndrome (AIDS), due o he Human Immunodeficiency Virus (HIV), widely recognized as one of he mos devasaing epidemic, has affeced people all over he world. According o a recen repor [], by he end of 9 he number of people living wih HIV reached 33.3 million and. million deahs were linked o AIDS []. HIV desroys CD+ T cell lymphocyes of he human immune sysem of he person infeced wih he virus, causing he immune sysem o weaken or become immune deficien. As has now become well known, HIV infecion ypically follows a hree phase paern, ha is, he primary response phase (acue phase), he clinical laency phase (chronic phase), and he final phase of onse of AIDS. Alhough here is no cure for AIDS so far, a variey of drugs can be used o slow he progress of he disease by decreasing he rae of viral growh or replicaion or he recovery of CD+ T cell lymphocyes. Anireroviral drugs are he main alernaive reamen for HIV infecion and AIDS. Highly Acive Anireroviral Therapy (HAART) is a combinaion of hree or more anireroviral drugs, which is, during reamen, effecive in conrolling he viral loads of HIV in he paien's body a a low level and improving he immune sysem [3], []. However, on inerruping HAART here is a rebound of plasma viral loads [5] so ha he use of his reamen has been linked o meabolic side effecs in humans []. There are evidence ha such paiens may be a increased risk for opporunisic infecions [7]. Thus, in order o avoid he problems wih drug reamen, an alernaive reamen is needed. Aphaeresis has for some ime been used effecively in he reamen of hepaiis C infecion []-[], cancer [] and HIV infecion []. lasma aphaeresis is a process in which he virus in he large molecular componens of plasma are removed from a paien while he small molecular componens of plasma and cell componens of blood are reurned o he paien. Several sudies sugges ha plasma aphaeresis may offer a good alernaive for he reamen of AIDS paiens wih peripheral polyneuropahy [3] [5]. A sudy by Ramranam e al. [] showed ha plasma aphaeresis can Issue 3, Volume 7, 3 9

2 reduce he viral load o half of he original load in he blood. However, plasma virus rebounds a baseline load afer he end of aphaeresis []. Since he viral populaion circulaes beween he lymph node and plasma comparmens, he viral load influences he dynamics of HIV infecion. Therefore, in order o use he plasma aphaeresis reamen, i is essenial o sudy he effec of his echnique on he dynamics of viral load in boh he lymph node and blood comparmens as well as he developmen of he virus-immune response in he human body. Many researchers have used mahemaical models o describe he populaion dynamics of cells involved in he immune response sysem relevan o HIV proliferaion [- ]. Mos models are based on sysems of ordinary differenial equaions (ODES) and parial differenial equaions (DES) [], []-[]. However, since he developmen of he disease ypically exhibis hree phases of infecion, hese models are insufficien o describe he hree differen ime scales and hard o consruc o simulae he enire course of he HIV infecion. Recenly, cellular auomaa (CA) models have become useful in modelling HIV infecion in he lymph node [7]- [9]. Alhough hese CA models have been capable of simulaing he hree phase paern of HIV dynamics observed clinically, mos of hese CA models only incorporaed he lymph node comparmen ino he simulaion. However, mos clinical sudies follow he disease progression based on blood daa. Since viral populaion circulaes beween he lymph node and plasma comparmens, viral load in boh comparmens are vial for he accurae diagnosic descripion of he dynamics of HIV progression. For his reason, Moonchai and enbury [,] [3] have proposed a double laiced CA simulaion model o invesigae he dynamics of HIV infecion in boh he lymph node and blood comparmens. In his paper, we modify he CA rules based on he CA model of Moonchai and enbury [] in order o invesigae he effec, on he CD+ T cell coun and viral load in boh he lymph node and blood comparmens, of differen clearance raes in plasma aphaeresis reamen, by incorporaing is applicaion in he viral load model in blood comparmen. Exending he work presened in [3], apar from discovering he effec of differen reamen proocols on he oucome of he plasma aphaeresis herapy, we also simulae he case where he reamen is abandoned afer a sufficienly long period of reamen. II. CA MODE OF HIV INFECTION As deailed in [3], cellular auomaa (CA) models are discree mahemaical models in which space is divided ino regular spaial cells, and ime progresses in discree seps. Each cell has one of a finie number of saes. The sae of each cell is updaed according o given local rules, ha is, he sae of a cell a a given ime depends on is own sae and he saes of is neighbours a he previous ime sep [3]. In his work, based on he CA model of Moonchai and enbury [], we consruc a CA model of HIV infecion in he lymph node and he peripheral blood comparmens or laices under plasma aphaeresis herapy. Model simulaions have been performed in MATA, and averaged over 5 runs for each configuraion. In each comparmen, he CA model is defined on a square laice of size, assuming he Moore s neighborhood using a neighborhood of range. The saes of he cells in each of he laices are updaed a each ime sep in parallel according o given rules, each ime sep corresponding o one week. Each sie on he laice is occupied by a cell which is assigned one of he five saes ha describe he possible saes in which hose cells may be found: non-acivaed cells, acive healhy cells (represening CD + T cells which are he main arge of he HIV), infeced A cells (being infeced cells ha are free o spread he infecion), infeced A cells (corresponding o infeced cells in he final sage of infecion before dying due o he acion of he immune response) or dead cells. The simulaion seps sar wih N non-acivaed cells, H healhy acive cells, and a small fracion HIV of infeced A cells (A ), such ha A HIV H, disribued randomly. Se iniial configuraion:, N, H,V, V, V, op, HIV, infec, repl, nona r, r, R,, T, =, d = av * v v v * * r r ( v ) * ( e ), * r ( ), Updae Healhy, A cells C = +, d = d + A Randomize r, (i, j), i, j Updae Inacive, A cells C All cells updaed Find new V Is < T and V N - number of inacive cells a ime H - number of healhy cells a ime A - number of infeced A cells a ime A - number of infeced A cells a ime D - number of dead cells a ime 3 Updae Dead cell C3 STO Issue 3, Volume 7, 3 95

3 Flowchar. The algorihm o updae all cells in each comparmen (coninued in Flowchar.). 3 Dead cell Inacive cell Infeced A cell r repl Has an A or A neighbors r op d A A A A d r nona Remains dead cell r infec repl Remains inacive N N D D A A D D H H D D H H N N Remains A C3 C Flowchar 3. The deail in he algorihm o updae all cells in each comparmen (coninued from Flowchar ). Table. Model parameers in he CA model in he lymph node. Infeced A cell A A D D Healhy cell r * v Has an A neighbor r * A A H H Has R A neighbors Remains healhy C r * A A H H N - number of inacive cells a ime H - number of healhy cells a ime A - number of infeced A cells a ime A - number of infeced A cells a ime D - number of dead cells a ime Flowchar. The deail in he algorihm o updae all cells in each comparmen (coninued from Flowchar ). Symbol Definiion Value [reference] aice size 5 N Number of nonacivaed or 5, nonproliferaing cells a H Number of healhy acive cells a 5, robabiliy or percenage of iniial.5 HIV op infeced cells robabiliy for a non-proliferaing cell o be replaced wih an acive healhy cell []. (esimaed) V Consan in probabiliy for a healhy cell o come in conac wih a virus.5 (esimaed) a Consan in v * r Consan in * (esimaed) r Consan in * (esimaed) Time delay for an infeced A cell o become an infeced A cell [] infec robabiliy for a healhy cell o be replaced wih an infeced A cell 5 [] robabiliy for a deah cell o be.99 repl replaced wih a healhy cell [] nona robabiliy for a deah cell o be replaced wih nonacivaed cells.9 (esimaed) R Number of infeced A cells in a cell neighbourhood o induce a healhy cell o become an infeced A cell [] Issue 3, Volume 7, 3 9

4 Table. Model parameers in he CA model in he blood comparmens. Symbol Definiion Value [reference] aice size N Number of nonacivaed or, nonproliferaing cells a H Number of healhy acive cells, a HIV robabiliy or percenage of iniial infeced cells.5 [] op robabiliy for a nonproliferaing. cell o be replaced (esimaed) wih an acive healhy cell V Consan in probabiliy for a healhy cell o come in conac wih a virus a Consan in v * r Consan in *.5 (esimae d).997 (esimaed) r Consan in * (esimaed) Time delay for an infeced A cell o become an infeced A cell [] infec robabiliy for a healhy cell o be replaced wih an infeced A cell robabiliy for a deah cell o be repl replaced wih a healhy cell nona robabiliy for a deah cell o be replaced wih nonacivaed cells R Number of infeced A cells in a cell neighbourhood o induce a healhy cell o become an infeced A cell 5 [].99 [].9 (esimaed) [] A each ime sep, all cells are updaed using he rules given in [] and [3]. Tha is, each of he cells is updaed according he rules which are described in Flowchars -3. The same rules are applied o updae he cells in boh he lymph node laice and he peripheral blood laice. The parameer values appearing in he flowchars used in our simulaions are given in Tables -. III. MODE FOR VIRA OAD In our CA model, he dynamics of he healhy and infeced cells are influenced by he viral load hrough he probabiliy * v. We calculae he viral load in he lymph node comparmen ( V ) and peripheral blood comparmen ( V ) a ime by using he following difference equaions. In he lymph node comparmen V V ps I ( V V ) c H V cv () H where = virus-producing infeced cells I = A A In he blood comparmen V ev V V V ps I ( V V ) c H V cv + F( ) () H where V, T kt, k,,,... F (), oherwise I = virus-producing infeced cells = A A V e V V = week (ime sep) T = duraion of a break beween reamens Table 3. Definiion and values of model parameers in he viral load simulaion. Value Symbol Definiion [reference] V lasma virus concenraion a [] (can vary) V Virus concenraion in he lymph node a p Average virion producion rae per infeced cell [] S Scaling facor in he lymph /H node (esimaed) S Scaling facor in he blood, / H c Clearance rae of free virus in H he lymph node c Clearance rae of free virus in H he blood (3) (esimaed). (esimaed). (esimaed) c Free virus deah rae.3 [] e Circulaion fracion of virus. beween lymph node and [3] blood Scaling facor: 7 lymph node blood [] Scaling facor: 5 lymph node blood [] Clearance rae of free virus.5-.7 due o plasma pheresis. T Time a sar of reamen, T Duraion of breaks from reamen In Eq. () (3), A and A are he numbers a ime of A and A infeced cells in he lymph node, respecively, while Issue 3, Volume 7, 3 97

5 A and A are he corresponding amouns in he blood. H and H are he numbers of healhy cells in he respecive comparmens a ime, p is he average virion producion rae per infeced cell, e represens he circulaion of virus beween he wo comparmens, c is he deah rae of free virus, and is he rae of free virus clearance due o he removal by plasma aphaeresis reamen. IV. RESUT AND DISCUSSION The values of he parameers appearing in ()-(3) used in our viral load simulaions are given in Table 3. Some of he values in hese ables are he same as hose used in [9]-[3], bu some have been adjused for more realisic simulaion oucomes. The model has been simulaed a differen raes of free virus clearance due o plasma aphaeresis reamen. Averages over 5 simulaions have been obained using he parameric values in Tables and. When is se o zero, he model hen in fac simulaes he no reamen case. Firs, we simulae reamen which sars a wo differen sages of he disease, one of which sars a week (he final phase of he disease progression), he oher a week (he end poin of he clinical laency phase). The plasma aphaeresis herapy is simulaed by varying he value of he clearance rae and performed a a frequency of every weeks. The plos seen in Fig. show he dynamics of healhy cells, infeced A cells, infeced A cells, and dead cells in he lymph node and blood comparmens under he no reamen condiion. All hese graphs exhibi hree phases of he disease progression. Fig. -3 show he effec of he plasma aphaeresis reamen on healhy cells and viral load, respecively, in he lymph node and blood comparmens. In Fig. -3, he reamen is sared a T =. In he peripheral blood, i can be observed ha he level of healhy cells becomes higher han he no reamen level for a shor duraion afer he reamen has been preformed, while he viral load becomes lower during reamen. During he week breaks from reamen rebounds in he viral load o levels higher han he no reamen levels are eviden, which may lead o serious complicaions. There is he risk ha he reaed paien could be more vulnerable o opporunisic infecion during hese imes han an unreaed paien. Alhough he healhy cells curve is observed o become higher han he no reamen curve, he difference is in he order of 3 cells which is no, in our opinion, very significan. In Fig. -5, on he oher hand, where he reamen is iniiaed much earlier in he course of infecion, T =, he viral load does no appear o rebound o levels higher han he no reamen level, a leas if he reamen is kep up long enough. The simulaed curves of reaed paiens all drop below ha of he unreaed paien during he reamen, and remain a he lower levels even during he week breaks afer he reamen has been kep up for a while. Alhough he level of healhy cells in he peripheral blood comparmen is higher during reamen, he difference is again in he order of 3 cells. From his simulaion resuls, we may be able o deduce ha he plasma aphaeresis reamen could be more beneficial o he paien if i is iniiaed a an earlier sage in he progression of HIV infecion. healhy cells, infeced A cells, infeced A cells, and dead cells in he lymph node healhy cells, infeced A cells, infeced A cells, and dead cells in he peripheral blood viral load in he lymph node viral load in he peripheral blood ime (weeks) x 5 healhy cells infeced A cells infeced A cells dead cells 3 5 ime (weeks) 3 x 3 5 ime (weeks) x 5 healhy cells Infeced A cells Infeced A cells dead cells 3 5 ime (weeks) Fig. Simulaed dynamics, under he no reamen condiion, of (a) healhy cells, infeced A cells, infeced A cells, and dead cells in he lymph node, and (b) in he blood comparmens (c) viral load in he lymph node comparmen, and (d) in he peripheral blood comparmen. (a) (b) (c) (d) Issue 3, Volume 7, 3 9

6 H e alh y cells in h e lym p h n od e Healhy cells in he peripheral blood Viral load in he lymph node 3. x ime (weeks) 5 5. x no reamen =.5 =. =.7 no reamen =.5 =. =.7 no reamen =.5 =. = ime (weeks) ime (weeks) (a) (b) (c) Viral load in he peripheral blood Viral load in he peripheral blood Viral load in he peripheral blood x 5 x 5 x 5 no reamen = ime (weeks) no reamen = ime (weeks) no reamen = ime (weeks) Fig.. Simulaion of he HIV infecion, under plasma aphaeresis reamen sared a week, showing levels of (a) healhy cells in lymph node, (b) healhy cells in he peripheral blood (c) viral load in he lymph node (plos previously shown in roceedings paper by Moonchai and enbury [3].) Fig. 3. Simulaion of he HIV infecion, under plasma aphaeresis reamen sared a week, showing level of viral load in he peripheral blood for differen values of (plos previously shown in roceedings paper by Moonchai and enbury [3].) Issue 3, Volume 7, 3 99

7 5 x x 5 Healhy cells in he lymph node 5 prereamen no reamen =.5 =. =.7 Viral load in he peripheral blood prereamen no reamen =.5 Healhy cells in he peripheral blood Viral load in he lymph node 3 5 ime (weeks) prereamen no reamen =.5 =. = ime (weeks) 3 x prereamen no reamen =.5 =. = ime (weeks) Fig.. Simulaion of he HIV infecion, under plasma aphaeresis reamen sared a week, showing levels of (a) healhy cells in lymph node, (b) healhy cells in he peripheral blood (c) viral load in he lymph node (plos previously shown in roceedings paper by Moonchai and enbury [3].) Viral load in he peripheral blood 3 5 ime (weeks) Viral load in he peripheral blood x ime (weeks) x 5 prereamen no reamen =.7 prereamen no reamen =. 3 5 ime (weeks) Fig. 5. Simulaion of he HIV infecion, under plasma aphaeresis reamen sared a week, showing level of viral load in he peripheral blood for differen values of (plos previously shown in roceedings paper by Moonchai and enbury [3].) Issue 3, Volume 7, 3 3

8 Fig. -7 show he evoluion of HIV infecion for differen values of in which reamen is abandoned afer week 5. The resul indicaes ha viral load rebounds o values no differen from he no reamen case afer reamen ceases. The simulaed dynamics of healhy cells in he peripheral blood, seen in Fig. b), exhibis ineresing developmen afer reamen cessaion. For a cerain period afer he reamen has been abandoned, healhy cells in reaed paiens seem o mainain a higher level in he blood comparmen han ha of he unreaed paien (he red curve). This may be aken o reflec in favour of he reamen by plasma aphaeresis under our invesigaion. However, his favourable condiion appears, a leas in his paricular simulaion resul shown here, o las for only a relaively shor period afer he reamen has been abandoned. In fac, he black curve corresponding o he higher clearance rae. is observed o drop o a dangerously low level which could mean a criical siuaion for he paien. We observe in our simulaion resuls, some of which are shown above, ha under reamen he developmens of he healhy cells in he lymph node and he blood comparmens do no follow similar paerns. The level of healhy cells says coninuously high in he lymph node comparmen, which would lead us o conclude ha he monhly reamen can keep he paien in a beer condiion even during he breaks from reamens. However, if he blood comparmen is also aken ino consideraion, such conclusion canno be made, since he level of healhy cells flucuaes more significanly here. This illusraes he advanage of using a double comparmen insead of a single comparmen CA simulaion model. Moreover, we have invesigaed wha will happen if he reamen is abandoned afer a period of ime has passed. This is in fac wha happens in real pracices where a number of paiens do no mainain rigorous reamen schedule, for reasons of financial problems, or inconvenience. Some paiens break away from reamen for lenghy periods, insead of keeping up wih he regular schedule of reamen a once every monh. Some drop ou of he program and become unraceable. To expec all paiens o subjec hemselves a a sricly regular reamen schedule is no always plausible. Our simulaion shown in Fig. -7 illusraes a possible oucome of abandoning reamen for a lenghy period which could possibly have ominous oucome. This may be aribued o he fac ha plasma aphaeresis for a shor period leads o a fas drop in he viral load in he peripheral blood. The naural compensaion mechanism would lead o a fas ransfer of viral load from he lymph node comparmen o he blood comparmen o compensae for he recognized drop in is level. Such fas ransfer is wha leads o he rebound of he viral load which can overshoo he normal level of he no reamen case. If his happens when he healhy cell levels are already low and he viral load is already dangerously high, i could lead o a complee failure in he immune sysem and developmen o sympoms of full blown AIDS. Healhy cells in he lymph node Healhy cells in he peripheral blood Viral load in he lymph node 3. x x ime (weeks) no reamen =.5 =. no reamen =.5 = ime (weeks) no reamen =.5 =. 5 ime (weeks) Fig.. Simulaed evoluion under he plasmapheresis reamen sared a week for differen values of. The reamen is inerruped a week 5. (a), (b) los of he numbers of healhy cells in he lymph node and blood comparmens, respecively, (c) viral load in he lymph node comparmen. Issue 3, Volume 7, 3 3

9 Viral load in he peripheral blood Viral load in he peripheral blood x 5 x 5 no reamen = ime (weeks) no reamen = ime (weeks) plasma aphaeresis herapy offers a beer reamen for HIV paiens han HAART since he same rebounding of viral load is observed in boh reamens. The impacs of differen clearance raes can only be observed clearly in Fig. 5, where a higher clearance rae leads o lower viral load during reamens and does no rebound back o as high a level. However, he difference in is impac canno be as clearly seen in he simulaed curves of he healhy cells in he lymph node or he blood. V. CONCUSION We have uilized he echnique of cellular auomaa simulaion wih double laice o simulae he impacs of plasma aphaeresis reamen on paiens infeced wih HIV. Effecs of various clearance raes on he reamen oucome have been invesigaed. The reamen sared earlier sages of infecion appears o yield beer resul on he reaed paiens compared o he unreaed case. Moreover, reamen inerrupions are observed o possibly be poenially harmful o he paien once hey have gone hrough a period of reamens. To be furher invesigaed is he benefi of combining plasma aphaeresis and HAART, a possible herapy which migh overcome some of he reservaions we have in he case where he wo reamen mehods are performed separaely. Alhough his invesigaion has yielded several valuable insighs, he resuls are sill no definiely conclusive. Due o he probabilisic naure of he infecious process, he disease progression is highly non-deerminisic. More simulaions are needed and furher in deph invesigaion wih careful analyses of he simulaion resuls is necessary. I is clear, however, ha he echnique of CA modeling and simulaion offers a promising ool for he invesigaion of such complicaed process involving muliple probabilisic evens. Fig. 7. Simulaed evoluion of viral load in he blood comparmen under he plasma aphaeresis reamen sared a week for differen values of. The reamen is inerruped a week 5. Again, we emphasize he advanage of having simulaion resuls in boh he lymph node and he blood comparmens in comparison, since wihou he evidence of evoluion of he healhy cells and viral load in he blood comparmen, he arefacs we have been able o observe in our argumens above would no have been clearly idenified. In ligh of our simulaions presened here, he oucome of he reamen wih plasma aphaeresis, alhough appearing promising if he reamen could be insiued on a paien a an early enough sage of infecion, is sill doubful especially in he long run, or if he reamen is no mainained in a coninual fashion. Impacs of he frequency and he duraion of reamen or he breaks from reamens sill need o be invesigaed furher. These facors can poenially affec significanly he oucomes of such reamen. Moreover, for he same reason, i canno be concluded wih cerainy ha ACKWEDGMENT This work was suppored by Mahidol Universiy and he Cenre of Excellence in Mahemaics, CHE, Thailand. REFERENCES [] S. Moonchai, Y. enbury, W. Triampo, Cellular auomaa simulaion modeling of HIV infecion in lymph node and peripheral blood comparmens, Inernaional Journal of Mahemaics and Compuers in Simulaion, Vol., pp. -3,. [] UNAIDS () Unie for universal access: overview brochure on High evel Meeing on AIDS'. [3] H. Mohri, A.S. erelson, K. Tung, R.M. Ribeiro,. Ramranam, M. Markowiz, R. Kos, A. Hurley,. Weinberger, D. Cesar, M.K. Hellersein, D.D. Ho, Increased urnover of T lymphocyes in HIV- infecion and is reducion by anireroviral herapy, J. Exp. Med., Vol. 9, pp.77 7,. [] D.. Clifford, C. Yiannousos, M. Glicksman, D.M. Simpson, E.J. Singer,.J. iliero, C.M. Marra, G.S. Francis, J.C. McArhur, K.. Tyler, A.C. Tselis, N.E. Hyslop, HAART improves prognosis in HIVassociaed progressive muli- focal leukoencephalopahy, Neurology, Vol. 5, pp. 3 5, 999. [5]. Naverree, V. Morene, F. Garcia, redicors of onsillar issue HIV- viral burden a baseline and afer year of anireroviral herapy, Aniviral Therapy, Vol., pp , 3. Issue 3, Volume 7, 3 3

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